Compounds and methods for treating inflammatory and fibrotic disorders

ABSTRACT

Disclosed are compounds and methods for treating inflammatory and fibrotic disorders, including methods of modulating a stress activated protein kinase (SAPK) system with an active compound, wherein the active compound exhibits low potency for inhibition of the p38 MAPK; and wherein the contacting is conducted at a SAPK-modulating concentration that is at a low percentage inhibitory concentration for inhibition of the p38 MAPK by the compound. Also disclosed are derivatives and analogs of pirfenidone, useful for modulating a stress activated protein kinase (SAPK) system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.12/477,715, filed Jun. 3, 2009, now U.S. Pat. No. 8,304,413 which claimsthe benefit of U.S. Provisional Application No. 61/058,436, filed Jun.3, 2008, and U.S. Provisional Application No. 61/074,446, filed Jun. 20,2008, each of which is incorporated by reference in its entirety.

BACKGROUND

1. Field of the Invention

This invention relates to compounds and methods useful in treatingvarious inflammatory and fibrotic conditions, including those associatedwith enhanced activity of kinase p38.

2. Background of the Invention

A large number of chronic and acute conditions have been recognized tobe associated with perturbation of the inflammatory response. A largenumber of cytokines participate in this response, including IL-1, IL-6,IL-8 and TNFα. It appears that the activity of these cytokines in theregulation of inflammation may be associated with the activation of anenzyme on the cell signaling pathway, a member of the MAP kinase familygenerally known as p38 and also known as SAPK, CSBP and RK.

Several inhibitors of p38, such as NPC 31169, SB239063, SB203580,FR-167653, and pirfenidone have been tested in vitro and/or in vivo andfound to be effective for modulating inflammatory responses.

There continues to be a need for safe and effective drugs to treatvarious inflammatory conditions such as inflammatory pulmonary fibrosis.

SUMMARY

Disclosed herein are compounds of formula I

wherein M is N or CR¹; A is N or CR²; L is N or CR³; B is N or CR⁴; E isN or CX⁴; G is N or CX³; J is N or CX²; K is N or CX¹; a dashed line isa single or double bond, except when B is CR⁴, then each dashed line isa double bond;R¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl,alkenyl, cyano, sulfonamido, halo, aryl, alkenylenearyl, and heteroaryl;R² is selected from the group consisting of hydrogen, alkyl, haloalkyl,halo, cyano, aryl, alkenyl, alkenylenearyl, heteroaryl,haloalkylcarbonyl, cycloalkyl, hydroxylalkyl, sulfonamido, andcycloheteroalkyl or R² and R¹ together form an optionally substituted5-membered nitrogen-containing heterocyclic ring;R³ is selected from the group consisting of hydrogen, aryl,alkenylenearyl, heteroaryl, alkyl, alkenyl, haloalkyl, amino, andhydroxy;R⁴ is selected from the group consisting of hydrogen, alkyl, haloalkyl,cyano, alkoxy, aryl, alkenyl, alkenylenearyl, and heteroaryl; andX¹, X², X³, X⁴, and X⁵ are independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, halo, hydroxy, amino, aryl,cycloalkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl,cyano, aldehydro, alkylcarbonyl, amido, haloalkylcarbonyl, sulfonyl, andsulfonamide, or X² and X³ together form a 5- or 6-membered ringcomprising —O(CH₂)_(n)O—, wherein n is 1 or 2,with the proviso that when all of A, B, E, G, J, K, L, and M are not N,then (a) at least one ofX¹, X², X³, X⁴, and X⁵ is not selected from the group consisting ofhydrogen, halo, alkoxy, and hydroxy or (b) at least one of R¹, R², R³,or R⁴ is not selected from the group consisting of hydrogen, alkyl,alkenyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, substituted phenyl,halo, hydroxy, and alkoxyalkyl,or a pharmaceutically acceptable salt, ester, or solvate thereof.

In some embodiments, the compounds of formula (I) have a structure offormula (II) or (III):

wherein X⁶ and X⁷ are independently selected from the group consistingof hydrogen, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,alkylenylaryl, alkylenylheteroaryl, alkylenylheterocycloalkyl,alkylenylcycloalkyl, or X⁶ and X⁷ together form an optionallysubstituted 5 or 6 membered heterocyclic ring. In a specific class ofembodiments, the compound of formula (I) is a compound selected from thegroup recited in Table 1, below.

A compound disclosed herein preferably exhibits an IC₅₀ in the range ofabout 0.1 μM to about 1000 μM, and preferably about 1 μM to about 800μM, about 1 μM to about 500 μM, about 1 μM to about 300 μM, about 1 μMto about 200 μM, or about 1 μM to about 100 μM for inhibition of p38MAPK.

Also disclosed herein is a composition including the compound of formula(I) and a pharmaceutically acceptable excipient.

In another aspect, disclosed herein are methods of modulating a stressactivated protein kinase (SAPK) system by contacting a compounddisclosed herein with a p38 mitogen-activated protein kinase (MAPK),wherein the compound exhibits an IC₅₀ in the range of about 0.1 μM toabout 1000 μM for inhibition of the p38 MAPK; and wherein the contactingis conducted at a SAPK-modulating concentration that is less than anIC₃₀ for inhibition of the p38 MAPK by the compound. Contemplated p38MAPKs include, but are not limited to, p38α, p38β, p38γ, and p38δ. In apreferred composition, the concentration of the compound disclosedherein is effective to alter TNFα release in whole blood by at least15%.

In yet another aspect, disclosed herein are methods of modulating a SAPKsystem in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound as disclosedherein, wherein the compound exhibits an IC₅₀ in the range of about 0.1μM to about 1000 μM for inhibition of p38 MAPK; and the therapeuticallyeffective amount produces a blood or serum concentration of the compoundthat is less than an IC₃₀ for inhibition of p38 mitogen-activatedprotein kinase (MAPK). In some embodiments, the subject suffers from aninflammatory condition. The subject preferably is a mammal, morepreferably human. The compound can be administered to the subject on aschedule selected from the group consisting of three times a day, twicea day, once a day, once every two days, three times a week, twice aweek, and once a week.

For the compositions and methods described herein, preferred features,such as components, compositional ranges thereof, conditions, and steps,can be selected from the various examples provided herein.

DETAILED DESCRIPTION

It has now been discovered that a high therapeutic effect in treatingvarious disorders associated with enhanced activity of kinase p38 can beachieved by using a relatively low-potency p38 kinase inhibitorcompound.

Therefore, in one embodiment there is provided a method of modulating astress-activated kinase (SAPK) system by contacting a compound asdescribed herein with a p38 mitogen-activated protein kinase (MAPK). Apreferred compound exhibits an IC₅₀ in the range of about 0.1 μM toabout 1000 μM, and preferably about 1 μM to about 800 μM, about 1 μM toabout 500 μM, about 1 μM to about 300 μM, about 1 μM to about 200 μM, orabout 1 μM to about 100 μM for inhibition of p38 MAPK. The concentrationat which the compound is contacted with p38 MAPK is preferably less thanIC₃₀ for inhibition of the p38 by this compound.

Mitogen-activated protein kinases are evolutionarily conservedserine/threonine kinases involved in the regulation of many cellularevents. Several MAPK groups have been identified in mammalian cells,including extracellular signal-regulated kinase (ERK), p38, andSAPK/JNK. It is believed that MAPKs are activated by their specific MAPKkinases (MAPKKs): ERK by MEK1 and MEK2, p38 by MKK3 and MKK6, andSAPK/JNK by SEK1 (also known as MKK4) and MKK7 (SEK2). These MAPKKs mayalso be activated by various MAPKK kinases (MAPKKKs) such as Raf, MLK,MEKK1, TAK1, and ASK1.

It is believed that the MAPK network involves at least twelve clonedhighly conserved, proline-directed serine-threonine kinases which, whenactivated by cell stresses (e.g., oxidative stress, DNA damage, heat orosmotic shock, ultraviolet irradiation, ischemia-reperfusion), exogenousagents (e.g., anisomycin, Na arsenite, lipopolysaccharide, LPS) orpro-inflammatory cytokines, TNF-α and IL-1β, can phosphorylate andactivate other kinases or nuclear proteins such as transcription factorsin either the cytoplasm or the nucleus.

p38 MAPK

As used herein, “p38 MAPK” is a member (sub family) of thestress-activated protein kinase family, which includes at least 4isoforms (α, β, γ, δ), several of which are considered important inprocesses critical to the inflammatory response and tissue remodeling(Lee et al. Immunopharmacol. 47:185-201 (2000)). Unless indicatedotherwise, reference to “p38 MAPK,” “a p38 MAPK,” or “the p38 MAPK”contemplates any one, all, or a subset of the subfamily members. Thepredominant kinases in monocytes and macrophages, p38a and p38β, appearmore widely expressed compared to p38γ (skeletal muscle) or p38δ(testes, pancreas, prostate, small intestine, and in salivary, pituitaryand adrenal glands). A number of substrates of p38 MAP kinase have beenidentified including other kinases (MAPKAP K2/3, PRAK, MNK 1/2,MSK1/RLPK, RSK-B), transcription factors (ATF2/6, myocyte enhancerfactor 2, nuclear transcription factor-β, CHOP/GADD153, Elk1 andSAP-1A1) and cytosolic proteins (stathmin), many of which are importantphysiologically.

Jiang et al. J Biol Chem 271:17920-17926 (1996) reportedcharacterization of p38β as a 372-amino acid protein closely related top38α. Both p38α and p38β are activated by proinflammatory cytokines andenvironmental stress, p38β is preferentially activated by MAP kinasekinase-6 (MKK6) and preferentially activated transcription factor 2.Kumar et al. Biochem Biophys Res Comm 235:533-538 (1997) and Stein etal. J Biol Chem 272:19509-19517 (1997) reported a second isoform ofp38β, p38β2, containing 364 amino acids with 73% identity to p38α. It isbelieved that p38β is activated by proinflammatory cytokines andenvironmental stress, although the second reported p38β isoform, p38β2,appears to be preferentially expressed in the central nervous system(CNS), heart and skeletal muscle, compared to the more ubiquitous tissueexpression of p38α. Furthermore, it is believed that activatedtranscription factor-2 (ATF-2) is a better substrate for p38β2 than forp38α.

The identification of p38γ was reported by Li. et al. Biochem BiophysRes Comm 228:334-340 (1996) and of p38δ by Wang et al. J Biol Chem272:23668-23674 (1997) and by Kumar et al. Biochem Biophys Res Comm235:533-538 (1997). These two p38 isoforms (γ and δ) represent a uniquesubset of the MAPK family based on their tissue expression patterns,substrate utilization, response to direct and indirect stimuli, andsusceptibility to kinase inhibitors. It is believed that p38α and β areclosely related, but diverge from γ and δ, which are more closelyrelated to each other.

A characterization of p38 isoforms that are espressing in affectedtissue from patients with Rheumatoid Arthritis suggests that p38α and γare the most significantly expressed isoforms (Korb, Tohidats-Akrad,Cetin, Axmann, Smolen, and Schett, 2006, Arthritis and Rheumatism 54(9):2745-56). The authors found that p38α and γ were the predominantisoforms in macrophages, p38β and γ were expressed in synovialfibroblasts, and p38 δ was expressed in granulocytes. These data suggestthat p38 isoforms in addition to p38α is more broad than suggested bythe results of in initial studies.

Typically the p38 MAP kinase pathway is directly or indirectly activatedby cell surface receptors, such as receptor tyrosine kinases, chemokinesor G protein-coupled receptors, which have been activated by a specificligand, e.g., cytokines, chemokines or lipopolysaccharide (LPS) bindingto a cognate receptor. Subsequently, p38 MAP kinase is activated byphosphorylation on specific threonine and tyrosine residues. Afteractivation, p38 MAP kinase can phosphorylate other intracellularproteins, including protein kinases, and can be translocated to the cellnucleus, where it phosphorylates and activates transcription factorsleading to the expression of pro-inflammatory cytokines and otherproteins that contribute to the inflammatory response, cell adhesion,and proteolytic degradation. For example, in cells of myeloid lineage,such as macrophages and monocytes, both IL-1β and TNFα are transcribedin response to p38 activation. Subsequent translation and secretion ofthese and other cytokines initiates a local or systemic inflammatoryresponse in adjacent tissue and through infiltration of leukocytes.While this response is a normal part of physiological responses tocellular stress, acute or chronic cellular stress leads to the excess,unregulated, or excess and unregulated expression of pro-inflammatorycytokines. This, in turn, leads to tissue damage, often resulting inpain and debilitation.

In alveolar macrophages, inhibition of p38 kinases with p38 inhibitor,SB203580, reduces cytokine gene products. It is believed thatinflammatory cytokines (TNF-α, IFN-γ, IL-4, IL-5) and chemokines (IL-8,RANTES, eotaxin) are capable of regulating or supporting chronic airwayinflammation. The production and action of many of the potentialmediators of airway inflammation appear to be dependent upon thestress-activated MAP kinase system (SAPK) or p38 kinase cascade(Underwood et al. Prog Respir Res 31:342-345 (2001)). Activation of thep38 kinase pathway by numerous environmental stimuli results in theelaboration of recognized inflammatory mediators whose production isconsidered to be translationally regulated. In addition, a variety ofinflammatory mediators activate p38 MAPK which may then activatedownstream targets of the MAPK system including other kinases ortranscription factors, thus creating the potential for an amplifiedinflammatory process in the lung.

Downstream Substrates of p38 Group of MAP Kinases

Protein kinase substrates of p38α or p38β include MAP kinase-activatedprotein kinase 2 (MAPKAPK2 or M2), MAP kinase interaction protein kinase(MNK1), p38 regulated/activated kinase (PRAK), mitogen- andstress-activated kinase (MSK: RSK-B or RLPK).

Transcription factors activated by p38 include activating transcriptionfactor (ATF)-1, 2 and 6, SRF accessory protein 1 (Sap 1), CHOP (growtharrest and DNA damage inducible gene 153, or GADD153), p53, C/EBPβ,myocyte enhance factor 2C (MEF2C), MEF2A, MITF1, DDIT3, ELK1, NFAT, andhigh mobility group-box protein (HBP1).

Other types of substrates for p38 include cPLA2, Na+/H+ exchangerisoform-1, tau, keratin 8, and stathmin.

Genes regulated by the p38 pathway include c-jun, c-fos, junB, IL-1,TNF, IL-6, IL-8, MCP-1, VCAM-1, iNOS, PPARγ, cyclooxygenase (COX)-2,collagenase-1 (MMP-1), Collagenase-3 (MMP-13), HIV-LTR, Fg1-2, brainnatriuretic peptide (BNP), CD23, CCK, phosphoenolpyruvatecarboxy-kinase-cytosolic, cyclin D1, and LDL receptor (Ono et al.Cellular Signalling 12:1-13 (2000)).

Biological Consequences of p38 Activation

P38 and Inflammation:

Acute and chronic inflammation are believed to be central to thepathogenesis of many diseases such as rheumatoid arthritis, asthma,chronic obstructive pulmonary disease (COPD) and acute respiratorydistress syndrome (ARDS). The activation of the p38 pathway may play ancentral role in: (1) production of proinflammatory cytokines such asIL-1β, TNF-α and IL-6; (2) induction of enzymes such as COX-2, whichcontrols connective tissue remodeling in pathological condition; (3)expression of an intracellular enzyme such as iNOS, which regulatesoxidation; (4) induction of adherent proteins such as VCAM-1 and manyother inflammatory related molecules. In addition to these, the p38pathway may play a regulatory role in the proliferation anddifferentiation of cells of the immune system. p38 may participate inGM-CSF, CSF, EPO, and CD40-induced cell proliferation and/ordifferentiation.

The role of the p38 pathway in inflammatory-related diseases was studiedin several animal models Inhibition of p38 by SB203580 reduced mortalityin a murine model of endotoxin-induced shock and inhibited thedevelopment of mouse collagen-induced arthritis and rat adjuvantarthritis. A recent study showed that SB220025, which is a more potentp38 inhibitor, caused a significant dose-dependent decrease in vasculardensity of the granuloma. These results indicate that p38 or thecomponents of the p38 pathway can be a therapeutic target forinflammatory disease.

P38 and Fibrosis:

The uncontrolled and/or excessive deposition of extracellular matrix isa defining aspect of fibrotic diseases such as pulmonary fibrosis, livercirrhosis, renal fibrosis, and focal segmental glomerulosclerosis.Fibrosis is also an important factor in the progression and pathology ofdisease states that are not primarily considered to be fibroticdiseases. Several studies have implicated the p38 signaling cascade infibrosis. (Wang L, Ma R, Flavell R A, and Choi M E 2002 Journal ofBiological Chemistry 277: 47257-62; Stambe C, Atkins R C, Tesch G H,Masaki T, Schreiner G F, Nikolic-Paterson D J 2004 J. Am Soc Nephrol 15:370-9; Furukawa F, Matsuzaki K, et al 2003 Hepatology 38: 879-89).

p38 and Apoptosis:

It appears that concomitant activation of p38 and apoptosis is inducedby a variety of agents such as NGF withdrawal and Fas ligation. Cysteineproteases (caspases) are central to the apoptotic pathway and areexpressed as inactive zymogens. Caspase inhibitors may then block p38activation through Fas cross-linking. However, overexpression ofdominant active MKK6b can also induce caspase activity and cell death.The role of p38 in apoptosis is cell type- and stimulus-dependent. Whilep38 signaling has been shown to promote cell death in some cell lines,in different cell lines p38 has been shown to enhance survival, cellgrowth, and differentiation.

p38 in the Cell Cycle:

Overexpression of p38α in yeast leads to significant slowing ofproliferation, indicating involvement of p38α in cell growth. A slowerproliferation of cultured mammalian cells was observed when the cellswere treated with p38α/β inhibitor, SB203580.

p38 and Cardiomyocyte Hypertrophy:

Activation and function of p38 in cardiomyocyte hypertrophy has beenstudied. During progression of hypertrophy, both p38α and p38β levelswere increased and constitutively active MKK3 and MKK6-elicitedhypertrophic responses enhanced by sarcomeric organization and elevatedatrial natriuretic factor expression. Also, reduced signaling of p38 inthe heart promotes myocyte differentiation via a mechanism involvingcalcineurin-NFAT signaling.

p38 and Development:

Despite the non-viability of p38 knockout mice, evidence existsregarding the differential role of p38 in development. p38 has beenlinked to placental angiogenesis but not cardiovascular development inseveral studies. Furthermore, p38 has also been linked to erythropoietinexpression suggesting a role in erythropoiesis. PRAK has recently beenimplicated in cell development in murine implantation. PRAK mRNA, aswell as p38 isoforms, were found to be expressed throughout blastocystdevelopment

p38 and Cell Differentiation:

p38α and/or p38β were found to play an important role in celldifferentiation for several different cell types. The differentiation of3T3-L1 cells into adipocytes and the differentiation of PC12 cells intoneurons both require p38α and/or β. The p38 pathway was found to benecessary and sufficient for SKT6 differentiation into hemoglobinizedcells as well as C2C112 differentiation in myotubules.

p38 in Senescence and Tumor Suppression:

p38 has a role in tumorigenesis and senescence. There have been reportsthat activation of MKK6 and MKK3 led to a senescent phenotype dependentupon p38 MAPK activity. Also, p38 MAPK activity was shown responsiblefor senescence in response to telomere shortening, H₂O₂ exposure, andchronic RAS oncogene signaling. A common feature of tumor cells is aloss of senescence and p38 is linked to tumorigenesis in certain cells.It has been reported that p38 activation is reduced in tumors and thatloss of components of the p38 pathway such as MKK3 and MKK6 resulted inincreased proliferation and likelihood of tumorigenic conversionregardless of the cell line or the tumor induction agent used in thesestudies.

p38 MAP Kinase Inhibitors

A “p38 MAPK inhibitor” is a compound that inhibits the activity of p38.The inhibitory effects of a compound on the activity of p38 may bemeasured by various methods well-known to a skilled artisan. Forexample, the inhibitory effects may be measured by measuring the levelof inhibition of lipopolysaccharide (LPS)-stimulated cytokine production(Lee et al. Int J Immunopharmacol 10:835-843 (1988); Lee et al. Ann NYAcad Sci 696:149-170 (1993); Lee et al. Nature 372:739-746 (1994); Leeet al. Pharmacol Ther 82:389-397 (1999)).

Efforts to develop p38 MAPK inhibitors have focused on increasingpotency. SB203580 and other 2,4,5-triaryl imidazoles were found to bepotent p38 kinase inhibitors with IC₅₀ values in nanomolar range. Forexample, for SB203580 the IC₅₀ was found to be 48 nM. Thepyridinylimidazoles SKF 86002 (1) and SB203580 (2) shown below have beenused as the template for the majority of p38 inhibitors. Recentpublications (Lee et al. Immunopharmacology 47:185-201 (2000)) havedisclosed the p38 inhibitors (3-6) shown below. Notable among theseinhibitors is the relatively high potency and selectivity described forcompound 4 (p38 IC₅₀=0.19 nM) and the inhibition of inflammation drivenangiogenesis by SB 220025 (6).

Two p38 inhibitors reported to be in clinical development are HEP689 (7,anti-inflammatory for psoriasis and other skin disorders) and VX-745 (8,anti-inflammatory for rheumatoid arthritis).

Further discussion of new p38 inhibitors can be found in Boehm et al.Exp Opin Ther Pat 10:25-37 (2000); and Salituro et al. Curr Med Chem6:807-823 (1999).

Preferred p38 inhibitors described herein are pirfenidone derivativesand analogs that exhibit relatively low potency of p38 inhibition while,surprisingly, still having a relatively high therapeutic effect (e.g.,for modulating an SAPK system) as a result of such inhibition.Preferably, the p38 inhibitors of the embodiments exhibit IC₅₀ in therange of about 0.1 μM to about 1000 μM, or more preferably about 1 μM toabout 800 μM, about 1 μM to about 500 μM, about 1 μM to about 300 μM,about 1 μM to about 200 μM, or about 1 μM to about 100 μM for inhibitionof p38 MAPK.

Pirfenidone Derivatives and Analogs

Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) itself is a knowncompound and its pharmacological effects are disclosed, for example, inJapanese Patent Application KOKAI (Laid-Open) Nos. 87677/1974 and1284338/1976. U.S. Pat. Nos. 3,839,346; 3,974,281; 4,042,699; and4,052,509, each of which is hereby incorporated by reference in itsentirety, describe methods of manufacture of5-methyl-1-phenyl-2-(1H)-pyridone and its use as an anti-inflammatoryagent.

Pirfenidone and derivatives and analogs thereof are useful compounds formodulating a stress activated protein kinase (SAPK) system.

The term “alkyl” used herein refers to a straight or branched chainhydrocarbon group of one to ten carbon atoms, including, but not limitedto, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-hexyl, and the like. Alkyls of one to six carbon atoms are alsocontemplated. The term “alkyl” includes “bridged alkyl,” i.e., abicyclic or polycyclic hydrocarbon group, for example, norbornyl,adamantyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl,bicyclo[3.2.1]octyl, or decahydronaphthyl. Alkyl groups optionally canbe substituted, for example, with hydroxy (OH), halo, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, and amino. It is specifically contemplatedthat in the analogs described herein the alkyl group consists of 1-40carbon atoms, preferably 1-25 carbon atoms, preferably 1-15 carbonatoms, preferably 1-12 carbon atoms, preferably 1-10 carbon atoms,preferably 1-8 carbon atoms, and preferably 1-6 carbon atoms.

As used herein, the term “cycloalkyl” refers to a cyclic hydrocarbongroup, e.g., cyclopropyl, cyclobutyl, cyclohexyl, and cyclopentyl.“Heterocycloalkyl” is defined similarly as cycloalkyl, except the ringcontains one to three heteroatoms independently selected from the groupconsisting of oxygen, nitrogen, and sulfur. Nonlimiting examples ofheterocycloalkyl groups include piperidine, tetrahydrofuran,tetrahydropyran, dihydrofuran, morpholine, thiophene, and the like.Cycloalkyl and heterocycloalkyl groups can be saturated or partiallyunsaturated ring systems optionally substituted with, for example, oneto three groups, independently selected from the group consisting ofalkyl, alkyleneOH, C(O)NH₂, NH₂, oxo (═O), aryl, haloalkyl, halo, andOH. Heterocycloalkyl groups optionally can be further N-substituted withalkyl, hydroxyalkyl, alkylenearyl, or alkyleneheteroaryl.

The term “alkenyl” used herein refers to a straight or branched chainhydrocarbon group of two to ten carbon atoms containing at least onecarbon double bond including, but not limited to, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.

The term “halo” used herein refers to fluoro, chloro, bromo, or iodo.

The term “alkylene” used herein refers to an alkyl group having asubstituent. For example, the term “alkylene aryl” refers to an alkylgroup substituted with an aryl group. The alkylene group is optionallysubstituted with one or more substituent previously listed as anoptional alkyl substituent. For example, an alkylene group can be—CH₂CH₂—.

As used herein, the term “alkenylene” is defined identical as“alkylene,” except the group contains at least one carbon-carbon doublebond.

As used herein, the term “aryl” refers to a monocyclic or polycyclicaromatic group, preferably a monocyclic or bicyclic aromatic group,e.g., phenyl or naphthyl. Unless otherwise indicated, an aryl group canbe unsubstituted or substituted with one or more, and in particular oneto four groups independently selected from, for example, halo, alkyl,alkenyl, OCF₃, NO₂, CN, NC, OH, alkoxy, haloalkoxy, amino, CO₂H,CO₂alkyl, aryl, and heteroaryl. Exemplary aryl groups include, but arenot limited to, phenyl, naphthyl, tetrahydronaphthyl, chlorophenyl,methylphenyl, methoxyphenyl, trifluoromethylphenyl, nitrophenyl,2,4-methoxychlorophenyl, and the like.

As used herein, the term “heteroaryl” refers to a monocyclic or bicyclicring system containing one or two aromatic rings and containing at leastone nitrogen, oxygen, or sulfur atom in an aromatic ring. Unlessotherwise indicated, a heteroaryl group can be unsubstituted orsubstituted with one or more, and in particular one to four,substituents selected from, for example, halo, alkyl, alkenyl, OCF₃,NO₂, CN, NC, OH, alkoxy, haloalkoxy, amino, CO₂H, CO₂alkyl, aryl, andheteroaryl. Examples of heteroaryl groups include, but are not limitedto, thienyl, furyl, pyridyl, oxazolyl, quinolyl, thiophenyl,isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl,imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, andthiadiazolyl.

The term “haloalkyl” used herein refers to one or more halo groupsappended to an alkyl group.

The term “nitroalkyl” used herein refers to one or more nitro groupsappended to an alkyl group.

The term “thioalkyl” used herein refers to one or more thio groupsappended to an alkyl group.

The term “hydroxyalkyl” used herein refers to one or more hydroxy groupsappended to an alkyl group.

The term “alkoxy” used herein refers to straight or branched chain alkylgroup covalently bonded to the parent molecule through an —O— linkage.Examples of alkoxy groups include, but are not limited to, methoxy,ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, sec-butoxy, t-butoxy andthe like.

The term “alkoxyalkyl” used herein refers to one or more alkoxy groupsappended to an alkyl group.

The term “arylalkoxy” used herein refers to a group having an arylappended to an alkoxy group. A non-limiting example of an arylalkoxygroup is a benzyloxy(Ph-CH₂—O—).

The term “amino” as used herein refers to —NR₂, where R is independentlyhydrogen or alkyl. Non-limiting examples of amino groups include NH₂ andN(CH₃)₂.

The term “amido” as used herein refers to —NHC(O)alkyl or —NHC(O)H. Anon-limiting example of an amido group is —NHC(O)CH₃.

The term “carboxy” or “carboxyl” used herein refers to —COOH or itsdeprotonated form —COO⁻.

The term “alkoxycarbonyl” refers to —(CO)—O-alkyl. Examples ofalkoxycarbonyl groups include, but are not limited to, methoxycarbonylgroup, ethoxycarbonyl group, propoxycarbonyl group, and the like.

The term “alkylcarbonyl” refers to —(CO)-alkyl. Examples ofalkylcarbonyl groups include, but are not limited to, methylcarbonylgroup, ethylcarbonyl group, propylcarbonyl group, and the like.

The term “sulfonamido” refers to —SO₂NR₂ where R is independentlyhydrogen or an alkyl group. Examples of a sulfonamido group include, butare not limited to, —SO₂N(CH₃)₂ and —SO₂NH₂.

The term “sulfonyl” refers to —SO₂alkyl. One example of a sulfonyl groupis methylsulfonyl (e.g., —SO₂CH₃).

Carbohydrates are polyhydroxy aldehydes or ketones, or substances thatyield such compounds upon hydrolysis. Carbohydrates comprise theelements carbon (C), hydrogen (H) and oxygen (O) with a ratio ofhydrogen twice that of carbon and oxygen. In their basic form,carbohydrates are simple sugars or monosaccharides. These simple sugarscan combine with each other to form more complex carbohydrates. Thecombination of two simple sugars is a disaccharide. Carbohydratesconsisting of two to ten simple sugars are called oligosaccharides, andthose with a larger number are called polysaccharides.

The term “uronide” refers to a monosaccharide having a carboxyl group onthe carbon that is not part of the ring. The uronide name retains theroot of the monosaccharide, but the -ose sugar suffix is changed to-uronide. For example, the structure of glucuronide corresponds toglucose.

As used herein, a radical indicates species with a single, unpairedelectron such that the species containing the radical can be covalentlybonded to another species. Hence, in this context, a radical is notnecessarily a free radical. Rather, a radical indicates a specificportion of a larger molecule. The term “radical” can be usedinterchangeably with the term “group.”

As used herein, a substituted group is derived from the unsubstitutedparent structure in which there has been an exchange of one or morehydrogen atoms for another atom or group. When substituted, thesubstituent group(s) is (are) one or more group(s) individually andindependently selected from alkyl, cycloalkyl, aryl, fused aryl,heterocyclyl, heteroaryl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio,arylthio, cyano, halo, carbonyl, thiocarbonyl, alkoxycarbonyl, nitro,silyl, trihalomethanesulfonyl, trifluoromethyl, and amino, includingmono and di substituted amino groups, and the protected derivativesthereof. The protecting groups that can form the protective derivativesof the above substituents are known to those of skill in the art and canbe found in references such as Greene and Wuts, Protective Groups inOrganic Synthesis; 3^(rd) Edition, John Wiley and Sons: New York, 2006.Wherever a substituent is described as “optionally substituted” thatsubstituent can be substituted with the above-described substituents.

Asymmetric carbon atoms can be present. All such isomers, includingdiastereomers and enantiomers, as well as the mixtures thereof, areintended to be included in the scope of the disclosure herein. Incertain cases, compounds can exist in tautomeric forms. All tautomericforms are intended to be included in the scope of the disclosure herein.Likewise, when compounds contain an alkenyl or alkenylene group, thereexists the possibility of cis- and trans-isomeric forms of thecompounds. Both cis- and trans-isomers, as well as the mixtures of cis-and trans-isomers, are contemplated.

One family of such compounds is a compound of formula (I)

wherein M is N or CR¹; A is N or CR²; L is N or CR³; B is N or CR⁴; E isN or CX⁴; G is N or CX³; J is N or CX²; K is N or CX¹; a dashed line isa single or double bond, except when B is CR⁴, then each dashed line isa double bond;R¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl,alkenyl, cyano, sulfonamido, halo, aryl, alkenylenearyl, and heteroaryl;R² is selected from the group consisting of hydrogen, alkyl, haloalkyl,halo, cyano, aryl, alkenyl, alkenylenearyl, heteroaryl,haloalkylcarbonyl, cycloalkyl, hydroxyalkyl, sulfonamido, andcycloheteroalkyl or R² and R¹ together form an optionally substituted5-membered nitrogen-containing heterocyclic ring;R³ is selected from the group consisting of hydrogen, aryl,alkenylenearyl, heteroaryl, alkyl, alkenyl, haloalkyl, amino, andhydroxy;R⁴ is selected from the group consisting of hydrogen, alkyl, haloalkyl,cyano, alkoxy, aryl, alkenyl, alkenylenearyl, and heteroaryl; andX¹, X², X³, X⁴, and X⁵ are independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, halo, hydroxy, amino, aryl,cycloalkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl,cyano, aldehydro, alkylcarbonyl, amido, haloalkylcarbonyl, sulfonyl, andsulfonamide, or X² and X³ together form a 5- or 6-membered ringcomprising —O(CH₂)_(n)O—, wherein n is 1 or 2, with the proviso thatwhen all of A, B, E, G, J, K, L, and M are not N, then either (a) atleast one of X¹, X², X³, X⁴, and X⁵ is not selected from the groupconsisting of hydrogen, halo, alkoxy, and hydroxy or (b) at least one ofR¹, R², R³, or R⁴ is not selected from the group consisting of hydrogen,alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, phenyl, substitutedphenyl, halo, hydroxy, and alkoxyalkyl.

In some embodiments, only A is N. In various embodiments, only E and Jare each N. In some embodiments, only B is N. In various embodiments,only G is N. In some embodiments, only K is N. In various embodiments,only E is N. In some embodiments, only J is N. In some embodiments, onlyL is N. In various embodiments, only M is N.

In some embodiments, R¹ is selected from the group consisting ofhydrogen, 4-pyridyl, cyclopropanyl, 4-fluorophenyl, 2-furanyl, cyano,H₂NSO₂, (CH₃)₂NSO₂, 4-sulfonamido-phenyl, fluoro,4-(3,5-dimethyl)-isoxazolyl, 4-pyrazolyl, 4-(1-methyl)-pyrazolyl,5-pyrimidinyl, 1-piperazinyl, 1-morpholinyl, 1-pyrrolidinyl,2-imidazolyl, and thiazolyl.

In some embodiments, the compound of formula (I) is a compound offormula (II):

wherein at least one of R¹, R², R³, or R⁴ is not selected from the groupconsisting of hydrogen, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy,phenyl, substituted phenyl, halo, hydroxy, and alkoxyalkyl.

In some embodiments, R¹ and R² together form an optionally substituted5-membered nitrogen-containing heterocyclic ring. In a specific class ofembodiments, the compound of formula (I) is a compound of formula (III)or formula (IV):

wherein X⁸ is hydrogen or alkyl; X⁶ and X⁷ are independently selectedfrom the group consisting of hydrogen, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, alkylenylaryl, alkylenylheteroaryl,alkylenylheterocycloalkyl, alkylenylcycloalkyl, or X⁶ and X⁷ togetherform an optionally substituted 5 or 6 membered heterocyclic ring. Insome embodiments, X⁷ is hydrogen. In various embodiments, X⁸ is methyl.

In some embodiments, at least one of X¹, X², X³, X⁴, or X⁵ is alkyl, forexample, haloalkyl. In various embodiments, at least one of X¹, X², X³,X⁴, or X⁵ is alkenyl. In some embodiments, at least one of X¹, X², X³,X⁴, or X⁵ is amino. In various embodiments, at least one of X¹, X², X³,X⁴, A or X⁵ is thioalkyl. In some embodiments, at least one of X¹, X²,X³, X⁴, or X⁵ is aryloxy. In various embodiments, at least one of X¹,X², X³, X⁴, or X⁵ is arylalkoxy. In some embodiments, at least one ofX¹, X², X³, X⁴, or X⁵ is alkoxyalkyl. In various embodiments, at leastone of X¹, X², X³, X⁴, or X⁵ is alkylcarbonyl. In various embodiments,at least one of X¹, X², X³, X⁴, or X⁵ is amido. In some embodiments, atleast one of X¹, X², X³, X⁴, or X⁵ is sulfonyl.

Specific preferred compounds of formula (I) are listed in the followingTable 1.

TABLE 1 Cmpd No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375 Intentionally blank 376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

Synthetic Processes

The compounds of Formula (I) can be synthesized using known techniques.One means of synthesizing these compounds is via a Suzuki coupling, asshown in Scheme 1, and another is via an Ullmann condensation, as shownin Scheme 2. The starting reagents are chosen to provide the desiredsubstitutions in the final product. These reagents can themselves beprepared using known techniques or can be purchased from commercialsources, such as Sigma-Aldrich (Milwaukee, Wis.).

General Procedure A (Coupling):

A mixture of reagent A (0.5-1 mmol, 1 eq.), boronic acid B (2 eq.),copper(II) acetate (0.1-0.2 eq.), pyridine (2 eq.) and molecular sieves4 Å in dichloromethane (5 mL/1 mmol reagent A) is stirred overnight atroom temperature (e.g., 20-25° C.), opened to the air. The reaction ismonitored by TLC, and when no starting material is detected, thereaction mixture is washed with saturated sodium bicarbonate andethylenediaminetetraacetic acid (EDTA) and dried over sodium sulfate.Target products are isolated by prep-TLC (typically using ethylacetate/petroleum ether as solvent).

General Procedure B (Ulmann Condensation):

A mixture of reagent A (1 eq.), reagent B (1.2 eq.), copper iodide (CuI,0.2 eq.) and potassium carbonate (K₂CO₃, 2 eq) in dimethylformamide(DMF) is refluxed overnight under nitrogen. The reaction is monitored byTLC, and when no starting material is detected, the reaction mixture iswashed with saturated sodium bicarbonate, extracted with ethyl acetate(EA) and dried over sodium sulfate. Target products are isolated byprep-TLC.

In some embodiments, the intermediate aryl bromide for the Suzukicoupling is synthesized. A synthetic route is outlined in Scheme 3,below.

General Procedure C (Including Synthesis of Aryl Bromide Intermediate):

For some compounds, two Suzuki couplings are used to synthesize thefinal compound. The first intermediate aryl bromide is prepared asdescribed for General procedure A. Then, to a solution ofBr-substituted-1-phenyl-1H-pyridin-2-one (1 eq), a second boronic acid(1.2 eq), potassium carbonate (3.5 eq) and tricyclohexylphosphine (0.1eq) in toluene/water (2/1, v/v) under a nitrogen atmosphere is addedpalladium acetate (0.05 eq). The mixture is heated to 100° C. for 2-3 h,and then cooled to room temperature. Water is added, and the mixture isextracted with EA, the combined organics are washed with brine andwater, dried over anhydrous sodium sulfate, and concentrated in vacuo.The residue is purified by prep-TLC to afford the desired compound.

The compound can also be synthesized using a scheme as depicted below,where a triflate intermediate is used in the Suzuki coupling.

General Procedure D:

For step 1, the procedure is the same as for general procedure A. Forstep 2, a solution of the intermediate benzyl protected phenol (3.5 g,10.8 mmol) in methanol (200 ml) is added to a Pd/C (300 mg) catalystunder N₂ atmosphere, and then stirred for 2 h under H₂ atmosphere (1atm, 25° C.). The catalyst is filtered off through a celite pad, and thefiltrate is concentrated in vacuo to give the free phenolic hydroxyl.For step 3, a solution of the resulting phenol intermediate (2.2 g, 11.8mmol) in dichloromethane (DCM, 120 mL) is added to triethylamine (1.7 g,16.8 mmol) at −78° C., followed by the addition oftrifluoromethanesulfonic anhydride (4.76 g, 16.9 mmol). The resultingmixture is stirred at −78° C. for 15 min and quenched with ammoniumchloride solution (10 mL). After warming to room temperature, water (30mL) and DCM (50 mL) are added and separated. The target product isobtained by washing the crude mixture with methanol. For step 4, asolution of trifluoromethanesulfonic acid intermediate (0.79 mmol) andtetrakis(triphenylphosphine)palladium (0.011 g, 0.0095 mmol) indimethoxyethane (DME, 1 mL) is stirred at room temperature for 15 minfollowed by the addition of the solution arylboronic acid (0.21 mmol) inDME (1 mL) and 2M sodium carbonate (1 mL). The resulting mixture isrefluxed for 14 hr and cooled down to room temperature. Water and ethylacetate are added. After separation, the aqueous layer is extracted withethyl acetate. The combined ethyl acetate solution is dried over sodiumsulfate and filtered. The filtrate is concentrated in vacuo to dryness.Target products are isolated by prep-TLC.

General Procedure E:

(Alternative Suzuki coupling reaction conditions) To a solution of5-bromo-2-hydroxypyridine (1 eq.), corresponding boronic acid (1.2 eq),potassium carbonate (3.5 eq) and tricyclohexylphosphine (0.1 eq) intoluene/water (2:1, v:v) under nitrogen atmosphere is added palladiumacetate (0.05 eq). The mixture is heated to 100° C. for 2-3 h, and thencooled to room temperature, water is added and the mixture extractedwith EA; the combined organics are washed with brine, dried over sodiumsulfate, and concentrated in vacuo. Purification by prep-TLC affords thedesired 5-substituted-2-hydroxypyridine. The second coupling, a Suzukicoupling, of the intermediate 5-substituted-2-hydroxypyridine with anaryl boronic acid is performed following General Procedure A, asdescribed above.

In some embodiments, the compound of formula (I) has at least onefluorine atom as a substituent. Introduction of the fluorine can beaccomplished, as outlined in Scheme 6.

General Procedure F (Fluorination):

1 (1 eq) is dissolved in acetonitrile, diethyl amino sulfur trifluoride(DAST, 2.2 eq) is added, and fluorination is carried out at 80° C. in acapped plastic tube for 4 to 8 hours. After cooling to room temperature,the reaction mixture is diluted with DCM and poured into saturatedbicarbonate solution. The organic phase is separated and dried oversodium sulfate. The product is isolated by prep-TLC.

General Procedure G:

This procedure exemplified in Scheme 7, above. To a solution of 1 (3.0g, 16 mmol), 2 (2.5 g, 21 mmol), K₃PO₄ (12.5 g, 57 mmol) intoluene/water (60 mL/3 mL) under a nitrogen atmosphere is addedPd(PPh₃)₄ (2.0 g, 1.6 mmol). The mixture is heated to reflux for 3 h andthen cooled to room temperature. Water is added and the mixtureextracted with EA. The combined organics are washed with brine, driedover Na₂SO₄ and concentrated in vacuo. The product is isolated by columnchromatography to afford 3. 3 (2.0 g, 11 mmol) in HBr (aq. 40%)/ethanol(20 mL/4 mL) is heated to reflux for 2 h, and monitored by TLC. When nostarting material is detected, the mixture is cooled to roomtemperature, and neutralized by addition of NaHCO₃, extracted with EA,and then washed with brine, dried over Na₂SO₄ and concentrated in vacuoto afford 4. 5 is prepared using general procedure A.

General Procedure H:

In some embodiments, the compounds of formula I are prepared using aChan-Lam reaction, as depicted in Scheme 8, above. In one embodiment,the Chan-Lam synthetic procedure is as follows (Method H1A—where reagentA is a solid): to a solution of A (0.5 mmol) in 6 mL of DCM and 2 mL ofDMF, copper (II) acetate (1.0 mmol, 2 eq), boronic acid B (1.2 eq),pyridine (2 eq) and finely ground, activated 4 Å molecular sieves (600mg) are added. When the reagent A is a hydrobromide salt, TEA (2 mL) isadded. The mixture is stirred at room temperature in the open air for 12hours up to about 4 days. Additional boronic acid B can be added to thereaction mixture. Then, concentrated NH₄OH is added. The solvents areevaporated under vacuum, and the crude product absorbed on a silica padand purified by chromatographic column. In some specific cases, theproduct is further purified on reverse-phase preparative HPLC.

Alternatively, Method H1B starts with reagent A as a solution in DMF.This procedure is as follows: to a solution of A (2.5 mL of DMFsolution, 0.74 mmol) in 5 mL of DMF, copper (II) acetate (1.48 mmol, 2eq), boronic acid B (1.2 eq), pyridine (2 eq) and finely ground,activated 4 Å molecular sieves (600 mg) are added. The mixture isstirred at room temperature in the open air for 12 hours up to about 4days. Additional boronic acid B can be further added. Then, concentratedNH₄OH is added. The solvents are evaporated under vacuum, and the crudeproduct is absorbed on silica pad and purified by chromatographiccolumn. In some specific cases, the product is further purified onreverse-phase preparative HPLC.

In another procedure, the Chan-Lam reaction proceeds as follows (MethodH2): to a 0.3 M solution of A in DMF, copper (II) acetate (2 eq),boronic acid B (1.2 eq) and pyridine (2 eq) are added. The mixture isheated 1 h at 100° C. under microwave irradiation, then concentratedNH₄OH is added. The reaction mixture then is diluted with EA andfiltered through a celite pad. Solvents are evaporated, and the crudemixture absorbed on silica pad and purified by chromatographic column.In some specific cases, the product is further purified on reverse-phasepreparative HPLC.

General Procedure I:

Preparation of pyridones which are not commercially available can beachieved in the following manner, as outlined in Scheme 9.

The 5-bromo-2-methoxy-pyridine (1 eq), the boronic acid (1.2 eq) andK₂CO₃ (3 eq) were dissolved in a 10:1 mixture of DME/H₂O (4 ml/mmol).The solution was degassed by bubbling N₂ for 15 min and then Pd(PPh₃)₄(0.05 eq) was added. The reaction mixture was heated at 90° C. for 4-8 hand then cooled at room temperature, diluted with AcOEt and filtered ona celite plug. The filtrate was washed with brine. The separated organicphase was dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was purified by column chromatography.

General Procedure J:

Compounds of Formula III, as disclosed herein, are prepared as outlinedin Scheme 10.

Suzuki Coupling: General Procedure:

A mixture of the appropriate ester 8 (1 eq), the phenylboronic acid (1.2eq), copper(II) acetate (1.2 eq), pyridine (3 eq) and activated freshlycrushed 4A molecular sieves in 1,2-dichloroethane (21 mL/mmol of ester)is stirred, in an open vessel, for 4 days at room temperature. Themixture is filtered through celite and the solution thus obtained isevaporated under vacuum. The residue is dissolved DCM, washed with anaqueous NaHCO₃ solution, water, dried over Na₂SO₄ and concentrated undervacuum. Purification by flash chromatography (SiO₂; DCM:MeOH mixture)affords the desired compound 9.

Hydrolysis:

To a solution of the appropriate carboxylic ester 9 (1 eq) in a 1:1mixture of H₂O and THF (10 mL/mmol of ester), cooled to 0° C., a 6Maqueous solution of NaOH (10 eq) is added dropwise at 0° C. The reactionmixture is heated to 75° C. for 48 h. The remaining aqueous fraction,previously washed with Et₂O, is cooled at 0° C. and citric acid is addeduntil the pH is 3-4. The precipitate thus formed is filtered and washedwith plenty of water and Et₂O to afford the pure desired compound 10.

Amide Formation: General Procedure

A solution of the appropriate carboxylic acid 10 (150 mg, 0.44 mmol) ina 1:1 mixture of acetonitrile and EA (6 mL/mmol of acid), triethylamine(2 eq) is admixed. Pyrrolidine (1.2 eq) and TBTU (1.2 eq) are added. Thereaction mixture is stirred at room temperature for 12 h. The solventsare removed under vacuum and the crude thus obtained is re-dissolved inDCM. The organic layer is washed with 10% aqueous solution of NaHCO₃,brine, dried over Na₂SO₄ and evaporated under vacuum. Purification byflash chromatography (SiO₂; DCM:MeOH mixture) affords the pure desiredcompound 11 of Formula III.

General Procedure K (Synthesis of 8):

Preparation began with synthesis of 8 via either route A or route B.Route A is detailed in the following Scheme 11.

To a refluxing solution of di-tert-butyldicarbonate (211.7 g, 0.97 mol)in hexane (500 mL), a solution of 2-amino-3-methylpyridine (100 g,0.9247 mol) in AcOEt (150 mL) was added over 30 min. The mixture wasstirred at reflux temperature (65° C.) for an additional hour and thencooled to room temperature. The suspension was diluted with hexane (500mL) and stirred for 1 h at room temperature. The product was isolated byfiltration, washed with hexane and dried under vacuum to afford 130 g of2 (tert-butyl 3-methylpyridin-2-ylcarbamate) that was used in the nextstep without further purification.

A solution of 2 (50 g, 0.24 mol) in THF was cooled at −45° C. and a 1.3M solution of t-butyl lithium in pentane (500 mL, 0.65 mol) was addeddropwise. After 1 h the reaction temperature was decreased to −80° C.and diethyloxalate (105.22 g, 0.72 mol) was added. The reaction mixtureturned yellow and turbidity was observed. The mixture was kept at −50°C. for additional 2 h and then warmed at room temperature. The reactionwas quenched by slowly adding 700 mL of water and extracted with EA,washed with brine and dried over Na₂SO₄ to obtain 100 g of 3(1-tert-butyl2-(ethoxycarbonyl)-2-hydroxy-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate)as a crude orange oil.

Then, 3 (100 g) was dissolved in dry DCM (400 mL) and cooled at 0° C.TFA (300 mL) was added dropwise and the reaction mixture was stirredovernight. Volatile fractions were removed under vacuum and the residueTFA was neutralized with an aqueous solution of NaHCO₃. The pure 4(ethyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate, 25 g, 54% yield over twosteps) was obtained by filtration and washing with water.

Then, 4 (25 gm, 0.131 mol) was dissolved in acetonitrile (250 mL).4-dimethylamino pyridine (27.29 g, 0.22 mol) and a 4 M solution of BOCanhydride (48.83 g, 0.22 mol) in acetonitrile were added to the reactionmixture. The reaction mixture was stirred for 1 h. EA was added to thereaction, the organic phase was separated and washed with water, brine,dried over Na₂SO₄ and evaporated under vacuum. Purification by flashchromatography (SiO₂; DCM:MeOH 99:1) 20 g (52% yield) of pure 5(1-tert-butyl2-(ethoxycarbonyl)-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate) as anoff-white solid.

Next, to a solution of 5 (20 g, 0.064 mol) in DCM (200 mL) was addedmCPBA (77 g, 0.44 mol), and the reaction was stirred at room temperatureovernight. The mixture was purified by flash chromatography (SiO₂;DCM:MeOH 99:1) to afford 12 g (56% yield) of 6(1-(tert-butoxycarbonyl)-2-(ethoxycarbonyl)-1H-pyrrolo[2,3-b]pyridine7-oxide) as a colorless oil.

Then, 6 (12 g, 0.04 mol) was dissolved in acetic anhydride (120 mL) andrefluxed overnight. The reaction mixture was concentrated under vacuumand the residue was evaporated by addition of toluene to afford crude 7(ethyl 6-acetoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate) that wasdissolved in a 1:10:10 mixture of Et₃N:EtOH:H₂O and stirred overnight atroom temperature. The reaction mixture was concentrated under vacuum andEA was added. The precipitate thus formed was filtered and washed withEA to afford 2.8 g (35% yield) of pure 8 (ethyl6-oxo-6,7-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate).

Alternatively, 8 can be prepared following Route B, where 6a is madedirectly from 4, as shown in Scheme 12.

To a solution of 4 (25 g, 0.131 mol) in DCM (250 mL) mCPBA (90.5 g,0.525 mol) was added, and the reaction was stirred, at room temperature,overnight. The mixture was purified by flash chromatography (SiO₂;DCM:MeOH 95:5) to afford 24 g (88% yield) of 6a(2-(ethoxycarbonyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide) as a colorlessoil.

Then, 6a (24 g, 0.08 mol) was dissolved in acetic anhydride (240 mL) andthe reaction was refluxed overnight. The mixture was concentrated undervacuum and the residue was evaporated by addition of toluene to affordcrude 7 that was dissolved in a 1:10:10 mixture of Et₃N:EtOH:H₂O andstirred overnight at room temperature. The reaction mixture wasevaporated under vacuum and EA was added. The precipitate thus formedwas filtered and washed with EA to afford 9.6 g (40% yield) of pure 8.

General Procedure L:

Compounds as disclosed herein can be prepared using Buchwald-Hartwigcoupling, using aryl bromides. Appropriate aryl bromides can be preparedvia the following Scheme 13.

5-bromo-pyridin-2-one (1 eq.) is dissolved in DCM (5 mL/mmol of arylhalide) and N,N-dimethylformammide (0.7 mL/mmol of aryl halide). Theappropriate boronic acid (1.2 eq.), copper(II) acetate (2.0 eq.),pyridine (2.0 eq.) and 4 Å molecular sieves are added to the solutionand the reaction is stirred at room temperature in an open vessel for 3days. The reaction is monitored by UPLC-MS. At the end of the reaction aconcentrated solution of NH₄OH is added. Solvents are removed at reducedpressure and the crude is purified by flash chromatography (SiO₂; Pet.Ether/EtOAc mixture). The bromopyridone intermediate is then used in theBuchwald-Hartwig coupling either via Method L1 or Method L2.

Method L1 is as follows: ±BINAP (0.2 eq.) is suspended in dry toluene(7.5 mL/mmol of aryl halide) and dissolved at 80° C. After dissolution,the mixture is cooled to room temperature and Pd(OAc)₂ (0.1 eq) isadded. The mixture is stirred for 5 minutes, then the appropriatebromopyridone (1 eq.) is added, followed by the appropriate amine (5eq.) and NaOtBu (1.4 eq.). The reaction is heated at 80° C. for 15 h. 3NHCl is added, at room temperature, to the mixture and the aqueous phaseis separated and washed with EtOAc. The aqueous layer is then basifiedwith NH₄OH and back-extracted with EtOAc. The organic portions arecollected, dried over Na₂SO₄ and concentrated under reduced pressure.The crude is purified by flash chromatography (SiO₂: Pet. Ether/EtOAc3:1 up to pure EtOAc) then by reverse-phase preparative HPLC.

Method L2 is as follows: ±BINAP (0.2 eq.) is suspended in dry toluene(7.5 mL/mmol of aryl halide) and Pd₂dba₃ (0.1 eq) is added. The mixtureis stirred for 15 minutes, then the appropriate bromopyridone (1 eq.) isadded, followed by the appropriate amine (5 eq.) and NaOtBu (1.4 eq.).The reaction is heated at 80° C. for 15 h, and then cooled at roomtemperature. Solvents are evaporated and the crude product is purifiedby flash chromatography (SiO₂; Pet. Ether/EtOAc 3:1 up to pure EtOAc)then by reverse-phase preparative HPLC.

Other means of synthesizing the compounds of Formula I can be used. Aspirfenidone derivatives and analogs, these compounds can also besynthesized by any conventional reactions known in the art based on theknown synthetic schemes for pirfenidone, such as disclosed in U.S. Pat.Nos. 3,839,346; 3,974,281; 4,042,699; and 4,052,509.

Starting materials described herein are available commercially, areknown, or can be prepared by methods known in the art. Additionally,starting materials not described herein are available commercially, areknown, or can be prepared by methods known in the art. Startingmaterials can have the appropriate substituents to ultimately givedesired products with the corresponding substituents. Alternatively,substituents can be added at any point of synthesis to ultimately givedesired products with the corresponding substituents.

One skilled in the art will appreciate variations in the sequences and,further, will recognize variations in the appropriate reactionconditions from the analogous reactions shown or otherwise known whichmay be appropriately used in the processes described herein to make thecompounds of Formula I.

In the processes described herein for the preparation of the compoundsof Formula I, the use of protective groups is generally well recognizedby one skilled in the art of organic chemistry, and accordingly the useof appropriate protecting groups may in some cases be implied by theprocesses of the schemes herein, although such groups may not beexpressly illustrated. Introduction and removal of such suitableprotecting groups are well known in the art of organic chemistry; seefor example, T. W. Greene, Protective Groups in Organic Synthesis, Wiley(New York), 1999. The products of the reactions described herein may beisolated by conventional means such as extraction, distillation,chromatography, and the like.

The salts, e.g., pharmaceutically acceptable salts, of the compounds ofFormula I may be prepared by reacting the appropriate base or acid witha stoichiometric equivalent of the compounds of Formula I. Similarly,pharmaceutically acceptable derivatives (e.g., esters), metabolites,hydrates, solvates and prodrugs of the compounds of Formula I may beprepared by methods generally known to those skilled in the art. Thus,another embodiment provides compounds that are prodrugs of an activecompound. In general, a prodrug is a compound which is metabolized invivo (e.g., by a metabolic transformation such as deamination,dealkylation, de-esterification, and the like) to provide an activecompound. A “pharmaceutically acceptable prodrug” means a compound whichis, within the scope of sound medical judgment, suitable forpharmaceutical use in a patient without undue toxicity, irritation,allergic response, and the like, and effective for the intended use,including a pharmaceutically acceptable ester as well as a zwitterionicform, where possible, of the compounds of Formula I. Examples ofpharmaceutically-acceptable prodrug types are described in Higuchi andStella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.Symposium Series, and in Roche, ed., Bioreversible Carriers in DrugDesign, American Pharmaceutical Association and Pergamon Press, 1987,both of which are incorporated herein by reference.

The compounds and compositions described herein may also includemetabolites. As used herein, the term “metabolite” means a product ofmetabolism of a compound of the embodiments or a pharmaceuticallyacceptable salt, analog, or derivative thereof, that exhibits a similaractivity in vitro or in vivo to a compound of Formula I. The compoundsand compositions described herein may also include hydrates andsolvates. As used herein, the term “solvate” refers to a complex formedby a solute (herein, a compound of Formula I) and a solvent. Suchsolvents for the purpose of the embodiments preferably should notnegatively interfere with the biological activity of the solute.Solvents may be, by way of example, water, ethanol, or acetic acid. Inview of the foregoing, reference herein to a particular compound orgenus of compounds will be understood to include the various formsdescribed above, including pharmaceutically acceptable salts, esters,prodrugs, metabolites and solvates thereof.

Methods of Inhibiting p38 MAP Kinase

In an embodiment, methods are provided for modulating a SAPK system, invitro or in vivo. The methods include contacting a SAPK-modulatingconcentration of a compound with a p38 MAPK (e.g., by contacting thecompound with a cell or tissue containing the p38 MAPK), wherein thecompound has a relatively low potency for inhibition of the p38 MAPK,corresponding to a relatively high inhibitory concentration forinhibition of the p38 MAPK by the compound.

The inhibitory concentration (IC) is a concentration that results in areduction in the activity of p38 MAPK by a specified percentage (e.g.,50%, 40%, 30%, 20%, 10%) on a dose-response curve. For example, IC₅₀,IC₄₀, IC₃₀, IC₂₀ and IC₁₀ are determined as concentrations that resultin reductions in the activity of p38 MAPK by 50%, 40%, 30%, 20% and 10%,respectively on a dose-response curve. The IC₅₀ of the SAPKsystem-modulating compound is preferably in the range of about 0.1 μM toabout 1000 μM, and more preferably about 1 μM to about 800 μM, about 1μM to about 500 μM, about 1 μM to about 300 μM, about 1 μM to about 200μM, or about 1 μM to about 100 μM for inhibition of p38 MAPK. Thus, forexample, modulation of the SAPK system may involve contacting a compound(e.g., a compound of Formula I) with a p38 MAPK at a concentration thatis less than an IC₄₀, preferably less than IC₃₀, more preferably lessthan IC₂₀, even preferably less than IC₁₀ for inhibition of the p38 MAPKby the compound as determined on a concentration-response curve.

“Contacting a cell” refers to a condition in which a compound or othercomposition of matter is in direct contact with a cell or tissue, or isclose enough to induce a desired biological effect in a cell or tissue.For example, contacting a cell or tissue containing p38 MAPK with acompound may be conducted in any manner that permits an interactionbetween p38 MAPK and the compound, resulting in the desired biologicaleffect in a cell. Contacting a cell or tissue may be accomplished, forexample, by intermixing or administering a compound (such as a compoundof Formula I; and/or a salt, ester, prodrug and/or intermediate thereof,and/or a pharmaceutical composition comprising one or more of theforegoing).

Alternatively, contacting a cell or tissue may be accomplished byintroducing a compound in a manner such that the compound will betargeted, directly or indirectly, to a cell or tissue containing p38MAPK. Contacting a cell or tissue may be accomplished under conditionssuch that a compound binds to the p38 MAPK. Such conditions may includeproximity of the compound and p38-containing cell or tissue, pH,temperature, or any condition that affects the binding of a compound top38 MAPK.

In one class of embodiments, the cell is contacted with the compound invitro; in other embodiments, the cell is contacted with the compound invivo.

When the cell is contacted in vivo, the effective concentration (EC) isa concentration that results in a reduction in the activity of a p38MAPK by a specified percentage (e.g., 50%, 40%, 30%, 20%, 10%) asmeasured by a specific physiological response which depends on thereduction of the activity of the p38 MAPK. Such physiological responsemay be, for example, reduction in blood or other bodily fluidconcentration of TNFα. For example, EC₅₀, EC₄₀, EC₃₀, EC₂₀ and EC₁₀ aredetermined as concentrations that result in reductions in the activityof a p38 MAPK as measured by reduction in TNFα concentration by 50%,40%, 30%, 20% and 10%, respectively on a dose-response curve. The EC₅₀of the SAPK system-modulating compound is preferably in the range ofabout 100 μM to about 1000 μM, more preferably about 200 μM to about 800μM for inhibition of the p38 MAPK. Thus, for example, modulation of theSAPK system may involve contacting a compound (e.g., a compound ofFormula I) with a p38 MAPK at a concentration that is less than an EC₄₀,preferably less than EC₃₀, more preferably less than EC₂₀, evenpreferably less than EC₁₀ for inhibition of the p38 MAPK by the compoundas determined on a dose-response curve in vivo.

The compound can be provided in the form of a pharmaceuticalcomposition, together with a pharmaceutically acceptable carrier.

Screening a Library of Compounds for Low-Potency p38 Inhibitors

In another aspect, a method is provided for identifying apharmaceutically active compound, e.g., for determining whether acompound is potentially useful as a therapeutic agent, e.g., for theprevention or treatment of an inflammatory condition (such as a p38- orcytokine-associated condition). The method includes assaying a pluralityof compounds for inhibition of a p38 MAPK and selecting a compound whichexhibits a relatively low potency for inhibiting p38 MAPK. Preferably,an IC₅₀ of such a low-potency p38 inhibitor compound is in the range ofabout 0.1 μM to about 1000 μM, and more preferably about 1 μM to about800 μM, about 1 μM to about 500 μM, about 1 μM to about 300 μM, about 1μM to about 200 μM, or about 1 μM to about 100 μM for inhibition of p38MAPK. The plurality of compounds to be assayed is preferably selectedfrom a library of potential compounds. The assaying of the plurality ofcompounds from the library may be conducted in various ways. Forexample, in some embodiments, the methods further comprise contacting ap38 MAPK with the plurality of compounds, and determining whether thecompounds inhibit the activity of cytokines. The p38 MAPK is preferablyselected from the group consisting of p38α, p38β, p38γ, and p38δ. Inpreferred embodiments, the contacting step takes place in vitro. Inpreferred embodiments, the contacting step comprises contacting a cellcomprising p38 MAPK with the compound.

In yet another embodiment, methods are provided for inhibiting theactivity of a p38 MAPK in a cell, in vitro or in vivo. In general, suchmethods include contacting a cell containing a p38 MAPK with aneffective p38-inhibiting amount of a compound (e.g., a compound ofFormula I), under conditions such that p38 activity in the cell isinhibited. Examples of such methods are provided in the EXAMPLES sectionbelow. The compound preferably exhibits an IC₅₀ in the range of about0.1 μM to about 1000 μM, and more preferably about 1 μM to about 800 μM,about 1 μM to about 500 μM, about 1 μM to about 300 μM, about 1 μM toabout 200 μM, or about 1 μM to about 100 μM for inhibition of p38 MAPK.The contacting of the p38 MAPK with the compound is preferably conductedat a SAPK system-modulating concentration that is less than IC₃₀,preferably less than IC₂₀, more preferably less than IC₁₀ for inhibitionof the p38 MAPK by the compound.

In vivo methods include for example, introducing into a group of animalsorally or by injection a compound of interest (e.g., a compound ofFormula I) in various concentrations. Following the introduction of thecompound, lipopolysaccharide is administered intravenously. Serum TNFαlevels are measured and compared to that from control animals. Thepreferred compounds inhibit the release of TNFα, thus reducing TNFαlevels in the blood samples of the tested animals. The compoundpreferably exhibits an EC₅₀ in the range of about 100 μM to about 1000μM, preferably about 200 μM to about 800 μM for inhibition of therelease of TNFα. In some cases, the compound exhibits an EC₅₀ in therange of about 10 to about 100 μM.

The method of identifying a pharmaceutically active compound may furtherinclude determining a mammalian toxicity of the selected compound. Suchmethods are generally known to those skilled in the art. The method ofidentifying a pharmaceutically active compound may also includeadministering the selected compound to a test subject, either inconjunction with the determination of mammalian toxicity or for otherreasons. In an embodiment, the test subject test subject has or is atrisk for having an inflammatory condition. Preferably the test subjectis a mammal, and can be a human.

Methods of Treatment and/or Prevention

Another embodiment provides methods for treating or preventing diseasestates, e.g., inflammatory condition(s) and/or fibrotic conditions. Themethods include identifying a subject at risk for or having aninflammatory condition and/or fibrotic condition and administering acompound to the subject in an effective amount to treat or prevent theinflammatory and/or fibrotic condition. In preferred embodiments, thecompound exhibits an IC₅₀ in the range of about 0.1 μM to about 1000 μM,and more preferably about 1 μM to about 800 μM, about 1 μM to about 500μM, about 1 μM to about 300 μM, about 1 μM to about 200 μM, or about 1μM to about 100 μM for inhibition of p38 MAPK. In preferred embodiments,the effective amount produces a blood or serum or another bodily fluidconcentration that is less than an IC₃₀ or, preferably, an IC₂₀ or, morepreferably, an IC₁₀ for inhibition of a p38 MAPK by the compound. Inpreferred embodiments, the compound exhibits an EC₅₀ in the range ofabout 100 μM to about 1000 μM, preferably about 200 μM to about 800 μMfor inhibition of TNFα secretion. In other preferred embodiments, theeffective amount produces a blood or serum or another bodily fluidconcentration that is less than an EC₃₀ or, preferably, an EC₂₀ or, morepreferably, an EC₁₅ or, more preferably, an EC₁₀ for inhibition ofLPS-stimulated TNFα release in a bodily fluid by the compound. Theeffective amount is preferably about 70% or less, more preferably lessthan about 50%, of an amount that causes an undesirable side effect inthe subject, such as, but not limited to, drowsiness, gastrointestinalupset, and photosensitivity rash. The compound used for the treatment orprevention is preferably a compound of Formula I.

Methods for identifying a subject at risk for or having an inflammatorycondition are known to those skilled in the art. Examples ofinflammatory conditions that may be treated or prevented by the methodsdescribed herein include p38 associated conditions, e.g., conditionsassociated with altered cytokine activity, conditions associated withmodulation of a SAPK system, autoimmune diseases, and diseasesassociated with acute and chronic inflammation. The cytokine (orcytokines) is (are) preferably selected from the group consisting of,but not limited to, IL-1β, IL-6, IL-8, and TNFα. In an embodiment, thecompound used to treat or prevent the inflammatory condition is acompound that inhibits a kinase in the SAPK signaling pathway. Examplesof preferred compounds include a compound of Formula I.

The term “p38-associated condition” means a disease or other deleteriouscondition in which the p38 MAP kinase signaling pathway is implicated,whether directly or indirectly. Examples of p38-associated conditionsinclude conditions caused by IL-1β, TNFα, IL-6 or IL-8 dysregulation oroverexpression resulting from sustained, prolonged, enhanced or elevatedlevels of p38 activity. Such conditions include, without limitation,inflammatory diseases, autoimmune diseases, fibrotic diseases,destructive bone disorders, proliferative disorders, infectiousdiseases, neurodegenerative diseases, allergies, reperfusion ischemia instroke, heart attacks, angiogenic disorders, organ hypoxia, vascularhyperplasia, cardiac hypertrophy, thrombin-induced platelet aggregation,and conditions associated with the prostaglandin or cyclooxygenasepathways, e.g., conditions involving prostaglandin endoperoxidesynthase. A p38-associated condition can include any conditionassociated with or mediated by an isoform of p38.

A “fibrotic condition,” “fibroproliferative condition,” “fibroticdisease,” “fibroproliferative disease,” “fibrotic disorder,” and“fibroproliferative disorder” are used interchangeably to refer to acondition, disease or disorder that is characterized by dysregulatedproliferation or activity of fibroblasts and/or pathologic or excessiveaccumulation of collagenous tissue. Typically, any such disease,disorder or condition is amenable to treatment by administration of acompound having anti-fibrotic activity. Fibrotic disorders include, butare not limited to, pulmonary fibrosis, including idiopathic pulmonaryfibrosis (IPF) and pulmonary fibrosis from a known etiology, liverfibrosis, and renal fibrosis. Other exemplary fibrotic conditionsinclude musculoskeletal fibrosis, cardiac fibrosis, post-surgicaladhesions, scleroderma, glaucoma, and skin lesions such as keloids.

The term “modulating SAPK system” means increasing or decreasingactivity of the stress-activated protein kinase system activity, e.g.,by inhibiting p38 activity, whether in vitro or in vivo. In certainembodiments, the SAPK system is modulated when p38 activity in a cell isinhibited by about 50%, preferably by about 40%, more preferably byabout 30%, even more preferably by about 20%, or yet even morepreferably by about 10% compared to the p38 activity of an untreatedcontrol cell.

A condition associated with altered cytokine activity, as used herein,refers to a condition in which cytokine activity is altered compared toa non-diseased state. This includes, but is not limited to, conditionscaused by IL-1β, TNFα, IL-6 or IL-8 overproduction or dysregulationresulting in sustained, prolonged, enhanced or elevated levels ofcytokine activity, which may be associated with p38 activity. Suchconditions include, without limitation, inflammatory diseases,autoimmune diseases, fibrotic diseases, destructive bone disorders,proliferative disorders, infectious diseases, neurodegenerativediseases, allergies, reperfusion/ischemia in stroke, heart attacks,angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiachypertrophy, thrombin-induced platelet aggregation, and conditionsassociated with the cyclooxygenase and lipoxygenase signaling pathways,such as prostaglandin endoperoxide synthase. A cytokine-associatedcondition can include any condition associated with or mediated by IL-1(particularly IL-1β), TNFα, IL-6 or IL-8, or any other cytokine whichcan be regulated by p38. In preferred embodiments, the cytokineassociated condition is a condition associated with TNFα.

The methods described herein may also be used to treat autoimmunediseases and diseases associated with acute and chronic inflammation.These diseases include, but are not limited to: chronic obstructivepulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF),rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout,other arthritic conditions; sepsis; septic shock; endotoxic shock;gram-negative sepsis; toxic shock syndrome; myofacial pain syndrome(MPS); Shigellosis; asthma; adult respiratory distress syndrome;inflammatory bowel disease; Crohn's disease; psoriasis; eczema;ulcerative colitis; glomerular nephritis; scleroderma; chronicthyroiditis; Grave's disease; Ormond's disease; autoimmune gastritis;myasthenia gravis; autoimmune hemolytic anemia; autoimmune neutropenia;thrombocytopenia; pancreatic fibrosis; chronic active hepatitisincluding hepatic fibrosis; acute renal disease, chronic renal disease;renal fibrosis, irritable bowel syndrome; pyresis; restenosis; cerebralmalaria; stroke injury, ischemic injury; neural trauma; Alzheimer'sdisease; Huntington's disease; Parkinson's disease; acute pain, chronicpain; allergies, including allergic rhinitis and allergicconjunctivitis; cardiac hypertrophy, chronic heart failure; acutecoronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lymedisease; Reiter's syndrome; acute synoviitis; muscle degeneration,bursitis; tendonitis; tenosynoviitis; herniated, ruptured, or prolapsedintervertebral disk syndrome; osteopetrosis; thrombosis; silicosis;pulmonary sarcosis; bone resorption diseases, such as osteoporosis ormultiple myeloma-related bone disorders; cancer, including but notlimited to metastatic breast carcinoma, colorectal carcinoma, malignantmelanoma, gastric cancer, and non-small cell lung cancer;graft-versus-host reaction; and auto-immune diseases, such as MultipleSclerosis, lupus and fibromyalgia; AIDS and other viral diseases such asHerpes Zoster, Herpes Simplex I or II, influenza virus, Severe AcuteRespiratory Syndrome (SARS) and cytomegalovirus; and diabetes mellitus.In addition, the methods of the embodiments can be used to treatproliferative disorders (including both benign and malignanthyperplasias), including acute myelogenous leukemia, chronic myelogenousleukemia, Kaposi's sarcoma, metastatic melanoma, multiple myeloma,breast cancer, including metastatic breast carcinoma; colorectal,carcinoma; malignant melanoma; gastric cancer; non-small cell lungcancer (NSCLC); bone metastases, and the like; pain disorders includingneuromuscular pain, headache, cancer pain, dental pain, and arthritispain; angiogenic disorders including solid tumor angiogenesis, ocularneovascularization, and infantile hemangioma; conditions associated withthe cyclooxygenase and lipoxygenase signaling pathways, includingconditions associated with prostaglandin endoperoxide synthase-2(including edema, fever, analgesia, and pain); organ hypoxia;thrombin-induced platelet aggregation. In addition, the methodsdescribed herein may be useful for the treatment of protozoal diseasesin animals, including mammals.

A subject may include one or more cells or tissues, or organisms. Apreferred subject is a mammal. A mammal can include any mammal. Asnon-limiting examples, preferred mammals include cattle, pigs, sheep,goats, horses, camels, buffalo, cats, dogs, rats, mice, and humans. Ahighly preferred subject mammal is a human. The compound(s) can beadministered to the subject via any drug delivery route. Specificexemplary administration routes include oral, ocular, rectal, buccal,topical, nasal, ophthalmic, subcutaneous, intramuscular, intravenous(bolus and infusion), intracerebral, transdermal, and pulmonary.

The terms “therapeutically effective amount” and “prophylacticallyeffective amount,” as used herein, refer to an amount of a compoundsufficient to treat, ameliorate, or prevent the identified disease orcondition, or to exhibit a detectable therapeutic, prophylactic, orinhibitory effect. The effect can be detected by, for example, theassays disclosed in the following examples. The precise effective amountfor a subject will depend upon the subject's body weight, size, andhealth; the nature and extent of the condition; and the therapeutic orcombination of therapeutics selected for administration. Therapeuticallyand prophylactically effective amounts for a given situation can bedetermined by routine experimentation that is within the skill andjudgment of the clinician. Preferably, the effective amount of thecompound of the embodiments produces a blood or serum or another bodilyfluid concentration that is less than an IC₃₀, IC₂₀ or IC₁₀ forinhibition of p38 MAP kinase. Preferably, the effective amount of thecompound of the embodiments produces a blood or serum or another bodilyfluid concentration that is effective to alter TNFα secretion from wholeblood by 10%, 15%, 20%, 30%, 40% or 50%.

For any compound, the therapeutically or prophylactically effectiveamount can be estimated initially either in cell culture assays, e.g.,of neoplastic cells, or in animal models, usually rats, mice, rabbits,dogs, or pigs. The animal model may also be used to determine theappropriate concentration range and route of administration. Suchinformation can then be used to determine useful doses and routes foradministration in humans.

Therapeutic/prophylactic efficacy and toxicity may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., ED₅₀ (the dose therapeutically effective in 50% of thepopulation) and LD₅₀ (the dose lethal to 50% of the population). Thedose ratio between therapeutic and toxic effects is the therapeuticindex, and it can be expressed as the ratio, ED₅₀/LD₅₀. Pharmaceuticalcompositions that exhibit large therapeutic indices are preferred.However, pharmaceutical compositions that exhibit narrow therapeuticindices are also within the scope of the invention. The data obtainedfrom cell culture assays and animal studies may be used in formulating arange of dosage for human use. The dosage contained in such compositionsis preferably within a range of circulating concentrations that includean ED₅₀ with little or no toxicity. The dosage may vary within thisrange depending upon the dosage form employed, sensitivity of thepatient, and the route of administration.

More specifically, the maximum plasma concentrations (Cmax) can rangefrom about 0.1 μM to about 200 μM. Cmax can be about 0.5 μM to about 175μM, about 65 μM to about 115 μM, or about 75 μM to about 105 μM, orabout 85 μM to about 95 μM, or about 85 μM to about 90 μM depending uponthe route of administration. In some embodiments, Cmax can be about 1 μMto about 50 μM, about 1 μM to about 25 μM, about 1 μM to about 20 μM,about 1 μM to about 15 μM, about 1 μM to about 10 μM, about 1 μM toabout 5 μM. Specific Cmax values can be about 1 μM, about 2 μM, about 3μM, about 4 μM, about 5 μM, about 6 μM, about 7 μM, about 8 μM, about 9μM, about 10 μM, about 11 μM, about 12 μM, about 13 μM, about 14 μM,about 15 μM, about 16 μM, about 17 μM, about 18 μM, about 19 μM, about20 μM, about 21 μM, about 22 μM, about 23 μM, about 24 μM, or about 25μM. In general the dose will be in the range of about 100 mg/day toabout 10 g/day, or about 200 mg to about 5 g/day, or about 400 mg toabout 3 g/day, or about 500 mg to about 2 g/day, in single, divided, orcontinuous doses for a patient weighing between about 40 to about 100 kg(which dose may be adjusted for patients above or below this weightrange, particularly children under 40 kg). Generally the dose will be inthe range of about 1 mg/kg to about 100 mg/kg of body weight per day.

The exact dosage will be determined by the practitioner, in light offactors related to the subject that requires treatment. Dosage andadministration are adjusted to provide sufficient levels of the activeagent(s) or to maintain the desired effect. Factors which may be takeninto account include the severity of the disease state, general healthof the subject, age, weight, and gender of the subject, diet, time andfrequency of administration, drug combination(s), reactionsensitivities, and tolerance/response to therapy. Long-actingpharmaceutical compositions may be administered every 3 to 4 days, everyweek, or once every two weeks depending on half-life and clearance rateof the particular formulation.

It will be appreciated that treatment as described herein includespreventing a disease, ameliorating symptoms, slowing diseaseprogression, reversing damage, or curing a disease.

In one aspect, treating an inflammatory condition results in an increasein average survival time of a population of treated subjects incomparison to a population of untreated subjects. Preferably, theaverage survival time is increased by more than about 30 days; morepreferably, by more than about 60 days; more preferably, by more thanabout 90 days; and even more preferably by more than about 120 days. Anincrease in survival time of a population may be measured by anyreproducible means. In a preferred aspect, an increase in averagesurvival time of a population may be measured, for example, bycalculating for a population the average length of survival followinginitiation of treatment with an active compound. In an another preferredaspect, an increase in average survival time of a population may also bemeasured, for example, by calculating for a population the averagelength of survival following completion of a first round of treatmentwith an active compound.

In another aspect, treating an inflammatory condition results in adecrease in the mortality rate of a population of treated subjects incomparison to a population of subjects receiving carrier alone. Inanother aspect, treating an inflammatory condition results in a decreasein the mortality rate of a population of treated subjects in comparisonto an untreated population. In a further aspect, treating aninflammatory condition results a decrease in the mortality rate of apopulation of treated subjects in comparison to a population receivingmonotherapy with a drug that is not a compound of the embodiments, or apharmaceutically acceptable salt, metabolite, analog or derivativethereof. Preferably, the mortality rate is decreased by more than about2%; more preferably, by more than about 5%; more preferably, by morethan about 10%; and most preferably, by more than about 25%. In apreferred aspect, a decrease in the mortality rate of a population oftreated subjects may be measured by any reproducible means. In anotherpreferred aspect, a decrease in the mortality rate of a population maybe measured, for example, by calculating for a population the averagenumber of disease-related deaths per unit time following initiation oftreatment with an active compound. In another preferred aspect, adecrease in the mortality rate of a population may also be measured, forexample, by calculating for a population the average number of diseaserelated deaths per unit time following completion of a first round oftreatment with an active compound.

In another aspect, treating an inflammatory condition results in adecrease in growth rate of a tumor. Preferably, after treatment, tumorgrowth rate is reduced by at least about 5% relative to/number prior totreatment; more preferably, tumor growth rate is reduced by at leastabout 10%; more preferably, reduced by at least about 20%; morepreferably, reduced by at least about 30%; more preferably, reduced byat least about 40%; more preferably, reduced by at least about 50%; evenmore preferably, reduced by at least 60%; and most preferably, reducedby at least about 75%. Tumor growth rate may be measured by anyreproducible means of measurement. In a preferred aspect, tumor growthrate is measured according to a change in tumor diameter per unit time.

In another aspect, treating an inflammatory condition results in areduction in the rate of cellular proliferation. Preferably, aftertreatment, the rate of cellular proliferation is reduced by at leastabout 5%; more preferably, by at least about 10%; more preferably, by atleast about 20%; more preferably, by at least about 30%; morepreferably, by at least about 40%; more preferably, by at least about50%; even more preferably, by at least about 60%; and most preferably,by at least about 75%. The rate of cellular proliferation may bemeasured by any reproducible means of measurement. In a preferredaspect, the rate of cellular proliferation is measured, for example, bymeasuring the number of dividing cells in a tissue sample per unit time.

In another aspect, treating an inflammatory condition results in areduction in the proportion of proliferating cells. Preferably, aftertreatment, the proportion of proliferating cells is reduced by at leastabout 5%; more preferably, by at least about 10%; more preferably, by atleast about 20%; more preferably, by at least about 30%; morepreferably, by at least about 40%; more preferably, by at least about50%; even more preferably, by at least about 60%; and most preferably,by at least about 75%. The proportion of proliferating cells may bemeasured by any reproducible means of measurement. In a preferredaspect, the proportion of proliferating cells is measured, for example,by quantifying the number of dividing cells relative to the number ofnondividing cells in a tissue sample. In another preferred aspect, theproportion of proliferating cells is equivalent to the mitotic index.

In another aspect, treating an inflammatory condition results in adecrease in size of an area or zone of cellular proliferation.Preferably, after treatment, size of an area or zone of cellularproliferation is reduced by at least 5% relative to its size prior totreatment; more preferably, reduced by at least about 10%; morepreferably, reduced by at least about 20%; more preferably, reduced byat least about 30%; more preferably, reduced by at least about 40%; morepreferably, reduced by at least about 50%; even more preferably, reducedby at least about 60%; and most preferably, reduced by at least about75%. Size of an area or zone of cellular proliferation may be measuredby any reproducible means of measurement. In a preferred aspect, size ofan area or zone of cellular proliferation may be measured as a diameteror width of an area or zone of cellular proliferation.

The methods described herein may include identifying a subject in needof treatment. In a preferred embodiment, the methods include identifyinga mammal in need of treatment. In a highly preferred embodiment, themethods include identifying a human in need of treatment. Identifying asubject in need of treatment may be accomplished by any means thatindicates a subject who may benefit from treatment. For example,identifying a subject in need of treatment may occur by clinicaldiagnosis, laboratory testing, or any other means known to one of skillin the art, including any combination of means for identification.

As described elsewhere herein, the compounds described herein may beformulated in pharmaceutical compositions, if desired, and can beadministered by any route that permits treatment of the disease orcondition. A preferred route of administration is oral administration.Administration may take the form of single dose administration, or thecompound of the embodiments can be administered over a period of time,either in divided doses or in a continuous-release formulation oradministration method (e.g., a pump). However the compounds of theembodiments are administered to the subject, the amounts of compoundadministered and the route of administration chosen should be selectedto permit efficacious treatment of the disease condition.

The methods of the embodiments also include the use of a compound orcompounds as described herein together with one or more additionaltherapeutic agents for the treatment of disease conditions. Thus, forexample, the combination of active ingredients may be: (1) co-formulatedand administered or delivered simultaneously in a combined formulation;(2) delivered by alternation or in parallel as separate formulations; or(3) by any other combination therapy regimen known in the art. Whendelivered in alternation therapy, the methods described herein maycomprise administering or delivering the active ingredientssequentially, e.g., in separate solution, emulsion, suspension, tablets,pills or capsules, or by different injections in separate syringes. Ingeneral, during alternation therapy, an effective dosage of each activeingredient is administered sequentially, i.e., serially, whereas insimultaneous therapy, effective dosages of two or more activeingredients are administered together. Various sequences of intermittentcombination therapy may also be used.

Diagnostic tests are contemplated as part of the methods describedherein. For example, a tissue biopsy sample may be taken from a subjectsuffering from an inflammatory condition, e.g., a p38-associated orcytokine-associated condition. The biopsy sample can be tested todetermine the level of p38 activity (or cytokine levels) present in thesample; the sample can then be contacted with a selected compound of theinvention, and the p38 activity (or cytokine levels) measured todetermine whether the compound has a desired effect (e.g., inhibition ofp38 or cytokine activity with an IC₅₀ in the range of about 0.1 μM toabout 1000 μM, and preferably about 1 μM to about 800 μM, about 1 μM toabout 500 μM, about 1 μM to about 300 μM, about 1 μM to about 200 μM, orabout 1 μM to about 100 μM for inhibition of p38 MAPK). Such a test maybe used to determine whether treatment with such a compound is likely tobe effective in that subject. Alternatively, the sample may be contactedwith a labeled compound (e.g., a fluorescently-labeled compound, or aradioactivity-labeled compound) and the sample then examined and thefluorescent or radioactive signal detected to determine the distributionof p38 in the tissue sample. Repeated biopsy samples taken during acourse of treatment may also be used to study the efficacy of thetreatment. Other diagnostic tests using the compounds described hereinwill be apparent to one of ordinary skill in the art in light of theteachings of this specification.

Thus, for example, an embodiment provides methods for determining thepresence, location, or quantity, or any combination thereof of p38protein in a cell or tissue sample. The methods include: a) contactingthe cell or tissue sample with a compound of the invention underconditions such that the compound can bind to a p38 MAPK; and b)determining the presence, location, or quantity, or any combinationthereof of the compound in the cell or tissue sample, therebydetermining the presence, location, or quantity, or any combinationthereof of the p38 MAPK in the cell or tissue sample. Determining thepresence, location, or quantity, or any combination thereof of thecompound in the cell or tissue sample may be conducted by any means thatreveals the presence, location, or quantity, or any combination thereofof the compound in the cell or tissue. For example, as describedpreviously, radioactive or fluorescent labeling methods may be used.Additional methods of determining the presence, location, or quantity,or any combination thereof of the compound will be apparent to a skilledartisan.

Another embodiment provides methods for determining: (1) whether acompound will be a useful therapeutic agent for treatment of a subjectsuffering from an inflammatory condition, or (2) the severity of diseaseor (3) the course of disease during treatment with a disease-modifyingagent. The methods include: a) obtaining a cell or tissue sample fromthe subject before, during and after termination of treatment with acompound as described herein or another disease-modifying agent; b)contacting the sample with the compound; and c) determining the amountof the compound that binds to the sample, wherein binding to p38 MAPK bythe compound is related to the amount of p38 MAPK in the sample.

Specific Examples of Diseases Contemplated to be Treated by theCompounds and Methods Described Herein

COPD

Chronic obstructive pulmonary disease (COPD) is characterized by achronic inflammatory process in the lung that includes (1) increasednumber of inflammatory cells (neutrophils, macrophages and SD8⁺ T cells)in the airways and parenchyma, (2) increased inflammatory cytokine andchemokine expression, and (3) increased number of proteases (elastases,cathepsins, and matrix metalloproteinases, MMPs). The production andaction of many of potential mediators of airway inflammation arebelieved to be dependent on the stress-induced MAPK or p38 kinasecascade. Several reports support the association pf p38 kinaseactivation with as plethora of pulmonary events: LPS- and TNF-α-inducedintercellular adhesion molecule-1 expression on pulmonary microvascularendothelial cells, MMP-9 activation, hypoxia-induced stimulation ofpulmonary arterial cells, hyperosmolarity-induced IL-8 expression inbronchial epithelial cells, and enhanced eosinophil trafficking andsurvival.

Trifilieff et al. Brit J Pharmacol 144:1002-10 (2005) reported thatCGH2466, a combined adenosine receptor antagonist, p38 MAPK andphosphodiesterase type 4 inhibitor showed potent in vitro and in vivoanti-inflammatory activities in diseases such as asthma and COPD.Underwood et al. Am J Physiol Lung Cell Mol Physiol 279:L895-L902 (2000)demonstrated that the potent and selective p38 MAPK inhibitor, SB239063,reduced proinflammatory cytokine production, including IL-1β, TNF-α,IL-6, and IL-8, which have been linked to airway fibrosis because oftheir ability to regulate fibroblast proliferation and matrix productionthat leads to diminished neutrophil trafficking and activation in thelung. Earlier, the same compound was found capable of altering responsesassociated with chronic fibrosis induced by bleomycin. This inhibitoryactivity was selective for the α and β isoforms of the p38. Thecompounds and methods described herein are useful in the treatment ofCOPD.

Pulmonary Fibrosis

Pulmonary fibrosis also called idiopathic pulmonary fibrosis (IPF),interstitial diffuse pulmonary fibrosis, inflammatory pulmonaryfibrosis, or fibrosing alveolitis, is an inflammatory lung disorder anda heterogeneous group of conditions characterized by abnormal formationof fibrous tissue between alveoli caused by alveolitis comprising aninflammatory cellular infiltration into the alveolar septae withresulting fibrosis. The effects of IPF are chronic, progressive, andoften fatal. p38 MAPK activation has been demonstrated in the lung ofpatients with pulmonary fibrosis. A number of investigations aboutpulmonary fibrosis have indicated that sustained and augmentedexpression of some cytokines in the lung are relevant to recruitment ofinflammatory cells and accumulation of extracellular matrix componentsfollowed by remodeling of the lung architecture. In particular,proinflammatory cytokines such as TNF-α and interleukin IL-1β weredemonstrated to play major roles in the formation of pneumonitis andpulmonary fibrosis. In addition, profibrotic cytokines such as TGF-α andCTGF also play critical roles in the pathogenesis of pulmonary fibrosis.Matsuoka et al. Am J Physiol Lung Cell Mol Physiol 283:L103-L112 (2002)have demonstrated that a p38 inhibitor, FR-167653, ameliorates murinebleomycin-induced pulmonary fibrosis. Furthermore, pirfenidone, acompound with combined anti-inflammatory, antioxidant and antifibroticeffects was found effective in experimental models of pulmonary fibrosisas well as in clinical studies (see Raghu et al. Am J Respir Crit CareMed 159:1061-1069 (1999); Nagai et al. Intern Med 41:1118-1123 (2002);Gahl et al. Mol Genet Metab 76:234-242 (2002); Azuma et al. Am J RespirCrit Care Med 165:A729 (2002)). The compounds and methods describedherein are useful in the treatment of pulmonary fibrosis, such as IPF.

Renal Fibrosis

Irrespective of the nature of the initial insult, renal fibrosis isconsidered to be the common final pathway by which kidney diseaseprogresses to end-stage renal failure. Stambe et al. J Am Soc Nephrol15:370-379 (2004) tested an inhibitor of the active (phosphorylated)form of p38, NPC 31169, developed by Scios Inc. (San Francisco, Calif.)in a rat model of renal fibrosis, and reported a significant reductionin renal fibrosis assessed by interstitial volume, collagen IVdeposition, and connective tissue growth mRNA levels. The compounds andmethods described herein are useful in the treatment of renal fibrosis.

Leiomyoma

Uterine leiomyomas or fibroids are the most common pelvic tumors inwomen with no known long-term effective drug therapies available.Leiomyomas are characterized by increased cell proliferation and tissuefibrosis. Pirfenidone was tested on cell proliferation and collagenexpression in cultured myometrial and leiomyoma smooth muscle cells, andwas found to be an effective inhibitor of myometrial and leiomyoma cellproliferation (Lee et al. J Clin Endocrinol Metab 83:219-223 (1998)).The compounds and methods described herein are useful in the treatmentof leiomyomas.

Endomyocardial Fibrosis

Endomyocardial fibrosis (EMF) is a disorder characterized by thedevelopment of restrictive cardiomyopathy. EMF is sometimes consideredpart of a spectrum of a single disease process that includes Löfflerendocarditis (nontropical eosinophilic endomyocardial fibrosis orfibroplastic parietal endocarditis with eosinophilia). In EMF, theunderlying process produces patchy fibrosis of the endocardial surfaceof the heart, leading to reduced compliance and, ultimately, restrictivephysiology as the endomyocardial surface becomes more generallyinvolved. Endocardial fibrosis principally involves the inflow tracts ofthe right and left ventricles and may affect the atrioventricularvalves, leading to tricuspid and mitral regurgitation. MAPK activationwas shown to contribute to arrhythmogenic atrial structural remodelingin EMF. The compounds and methods described herein are useful in thetreatment and/or prevention of endomyocardial fibrosis.

Other Inflammatory Diseases

Many autoimmune diseases and diseases associated with chronicinflammation, as well as acute responses, have been linked to activationof p38 MAP kinase and overexpression or dysregulation of inflammatorycytokines. These diseases include, but are not limited to: rheumatoidarthritis; rheumatoid spondylitis; osteoarthritis; gout, other arthriticconditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis;toxic shock syndrome; asthma; adult respiratory distress syndrome;chronic obstructive pulmonary disease; chronic pulmonary inflammation;inflammatory bowel disease; Crohn's disease; psoriasis; eczema;ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute andchronic renal disease; irritable bowel syndrome; pyresis; restenosis;cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer'sdisease; Huntington's disease; Parkinson's disease; acute and chronicpain; allergic rhinitis; allergic conjunctivitis; chronic heart failure;acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lymedisease; Reiter's syndrome; acute synoviitis; muscle degeneration,bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsedintervertebral disk syndrome; osteopetrosis; thrombosis; cancer;restenosis; silicosis; pulmonary sarcosis; bone resorption diseases,such as osteoporosis; graft-versus-host reaction; and auto-immunediseases, such as Multiple Sclerosis, lupus and fibromyalgia; AIDS andother viral diseases such as Herpes Zoster, Herpes Simplex I or II,influenza virus and cytomegalovirus; and diabetes mellitus.

Many studies have shown that reducing the activity of p38 MAP kinase,its upstream activators or its downstream effectors, either throughgenetic or chemical means, blunts the inflammatory response and preventsor minimizes tissue damage (see, e.g., English, et al. Trends PharmacolSci 23:40-45 (2002); and Dong et al. Annu Rev Immunol 20:55-72 (2002)).Thus, inhibitors of p38 activity, which also inhibit excess orunregulated cytokine production and may inhibit more than a singlepro-inflammatory cytokine, may be useful as anti-inflammatory agents andtherapeutics. Furthermore, the large number of diseases associated withp38 MAP kinase-associated inflammatory responses indicates that there isa need for effective methods for treating these conditions.

Cardiovascular Disease.

Inflammation and leukocyte activation/infiltration play a major role inthe initiation and progression of cardiovascular diseases includingatherosclerosis and heart failure. Acute p38 mitogen-activated proteinkinase (MAPK) pathway inhibition attenuates tissue damage and leukocyteaccumulation in myocardial ischemia/reperfusion injury. The compoundsand methods described herein are useful for treating cardiovasculardisease.

Multiple Sclerosis.

Inflammation in the central nervous system occurs in diseases such asmultiple sclerosis and leads to axon dysfunction and destruction. Bothin vitro and in vivo observations have shown an important role fornitric oxide (NO) in mediating inflammatory axonopathy. p38 MAP kinaseis activated by NO exposure and inhibition of p38 signalling was shownto lead to neuronal and axonal survival effects. OCM and IGF-1 reducedp38 activation in NO-exposed cortical neurons and improved axon survivalin cultures exposed to NO, a process dependent on mitogen-activatedprotein kinase/extracellular signal-related kinase signalling. Thecompounds and methods described herein are useful for treating multiplesclerosis.

Primary Graft Nonfunction.

Nonspecific inflammation is associated with primary graft nonfunction(PNF). Inflammatory islet damage is mediated at least partially bypro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumornecrosis factor-α (TNF-α) produced by resident islet macrophages. Thep38 pathway is known to be involved in cytokine production in the cellsof the monocyte-macrophage lineage. Inhibition of the p38 pathway by achemical p38 inhibitor, SB203580, suppresses IL-1β and TNF-α productionin human islets exposed to lipopolysaccharide (LPS) and/or inflammatorycytokines. Although IL-1□β is predominantly produced by residentmacrophages, ductal cells and islet vascular endothelial cells werefound to be another cellular source of IL-1β in isolated human islets.SB203580 also inhibited the expression of inducible nitric oxidesynthase (iNOS) and cyclooxygenase-2 (COX-2) in the treated islets.Furthermore, human islets treated with SB203580 for 1 h prior totransplantation showed significantly improved graft function. Thecompounds and methods described herein are useful for improving graftsurvival in clinical islet transplantation.

Acute Renal Injury.

Cisplatin is an important chemotherapeutic agent but can cause acuterenal injury. Part of this acute renal injury is mediated through tumornecrosis factor-α (TNF-□α). Cisplatin activates p38 MAPK and inducesapoptosis in cancer cells. p38 MAPK activation leads to increasedproduction of TNF-□α a in ischemic injury and in macrophages. In vitro,cisplatin caused a dose dependent activation of p38 MAPK in proximaltubule cells. Inhibition of p38 MAPK activation led to inhibition ofTNF-α production. In vivo, mice treated with a single dose of cisplatindeveloped severe renal dysfunction, which was accompanied by an increasein kidney p38 MAPK activity and an increase in infiltrating leukocytes.However, animals treated with the p38 MAPK inhibitor SKF86002 along withcisplatin showed less renal dysfunction, less severe histologic damageand fewer leukocytes compared with cisplatin+vehicle treated animals.The compounds and methods described herein are useful for preventingacute renal injury.

Periodontitis.

The proinflammatory mediator bradykinin (BK) stimulates interleukin-8(IL-8) production in human gingival fibroblasts in vitro and plays animportant role in the pathogenesis of various inflammatory diseasesincluding periodontitis. The specific p38 mitogen-activated proteinkinase (MAPK) inhibitor SB 203580 reduced IL-8 production stimulated bythe combination of BK and IL-1β as well as the IL-1□β-stimulated IL-8production. The compounds and methods described herein are useful fortreating or preventing periodontitis.

Pharmaceutical Compositions

While it is possible for the compounds described herein to beadministered alone, it may be preferable to formulate the compounds aspharmaceutical compositions. As such, in yet another aspect,pharmaceutical compositions useful in the methods of the invention areprovided. More particularly, the pharmaceutical compositions describedherein may be useful, inter alia, for treating or preventinginflammatory conditions, e.g., conditions associated with p38 activityor cytokine activity or any combination thereof. A pharmaceuticalcomposition is any composition that may be administered in vitro or invivo or both to a subject in order to treat or ameliorate a condition.In a preferred embodiment, a pharmaceutical composition may beadministered in vivo. A subject may include one or more cells ortissues, or organisms. A preferred subject is a mammal A mammal includesany mammal, such as by way of non-limiting example, cattle, pigs, sheep,goats, horses, camels, buffalo, cats, dogs, rats, mice, and humans. Ahighly preferred subject mammal is a human.

In an embodiment, the pharmaceutical compositions may be formulated withpharmaceutically acceptable excipients such as carriers, solvents,stabilizers, adjuvants, diluents, etc., depending upon the particularmode of administration and dosage form. The pharmaceutical compositionsshould generally be formulated to achieve a physiologically compatiblepH, and may range from a pH of about 3 to a pH of about 11, preferablyabout pH 3 to about pH 7, depending on the formulation and route ofadministration. In alternative embodiments, it may be preferred that thepH is adjusted to a range from about pH 5.0 to about pH 8. Moreparticularly, the pharmaceutical compositions may comprise atherapeutically or prophylactically effective amount of at least onecompound as described herein, together with one or more pharmaceuticallyacceptable excipients. Optionally, the pharmaceutical compositions maycomprise a combination of the compounds described herein, or may includea second active ingredient useful in the treatment or prevention ofbacterial infection (e.g., anti-bacterial or anti-microbial agents).

Formulations, e.g., for parenteral or oral administration, are mosttypically solids, liquid solutions, emulsions or suspensions, whileinhalable formulations for pulmonary administration are generallyliquids or powders, with powder formulations being generally preferred.A preferred pharmaceutical composition may also be formulated as alyophilized solid that is reconstituted with a physiologicallycompatible solvent prior to administration. Alternative pharmaceuticalcompositions may be formulated as syrups, creams, ointments, tablets,and the like.

The term “pharmaceutically acceptable excipient” refers to an excipientfor administration of a pharmaceutical agent, such as the compoundsdescribed herein. The term refers to any pharmaceutical excipient thatmay be administered without undue toxicity.

Pharmaceutically acceptable excipients are determined in part by theparticular composition being administered, as well as by the particularmethod used to administer the composition. Accordingly, there exists awide variety of suitable formulations of pharmaceutical compositions(see, e.g., Remington's Pharmaceutical Sciences).

Suitable excipients may be carrier molecules that include large, slowlymetabolized macromolecules such as proteins, polysaccharides, polylacticacids, polyglycolic acids, polymeric amino acids, amino acid copolymers,and inactive virus particles. Other exemplary excipients includeantioxidants (e.g., ascorbic acid), chelating agents (e.g., EDTA),carbohydrates (e.g., dextrin, hydroxyalkylcellulose, and/orhydroxyalkylmethylcellulose), stearic acid, liquids (e.g., oils, water,saline, glycerol and/or ethanol) wetting or emulsifying agents, pHbuffering substances, and the like. Liposomes are also included withinthe definition of pharmaceutically acceptable excipients.

The pharmaceutical compositions described herein may be formulated inany form suitable for an intended method of administration. Whenintended for oral use for example, tablets, troches, lozenges, aqueousor oil suspensions, non-aqueous solutions, dispersible powders orgranules (including micronized particles or nanoparticles), emulsions,hard or soft capsules, syrups or elixirs may be prepared. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions, and suchcompositions may contain one or more agents including sweetening agents,flavoring agents, coloring agents and preserving agents, in order toprovide a palatable preparation.

Pharmaceutically acceptable excipients particularly suitable for use inconjunction with tablets include, for example, inert diluents, such ascelluloses, calcium or sodium carbonate, lactose, calcium or sodiumphosphate; disintegrating agents, such as cross-linked povidone, maizestarch, or alginic acid; binding agents, such as povidone, starch,gelatin or acacia; and lubricating agents, such as magnesium stearate,stearic acid or talc.

Tablets may be uncoated or may be coated by known techniques includingmicroencapsulation to delay disintegration and adsorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample celluloses, lactose, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with non-aqueousor oil medium, such as glycerin, propylene glycol, polyethylene glycol,peanut oil, liquid paraffin or olive oil.

In another embodiment, pharmaceutical compositions may be formulated assuspensions comprising a compound of the embodiments in admixture withat least one pharmaceutically acceptable excipient suitable for themanufacture of a suspension.

In yet another embodiment, pharmaceutical compositions may be formulatedas dispersible powders and granules suitable for preparation of asuspension by the addition of suitable excipients.

Excipients suitable for use in connection with suspensions includesuspending agents (e.g., sodium carboxymethylcellulose, methylcellulose,hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone,gum tragacanth, gum acacia); dispersing or wetting agents (e.g., anaturally occurring phosphatide (e.g., lecithin), a condensation productof an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate),a condensation product of ethylene oxide with a long chain aliphaticalcohol (e.g., heptadecaethyleneoxycethanol), a condensation product ofethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride (e.g., polyoxyethylene sorbitan monooleate)); andthickening agents (e.g., carbomer, beeswax, hard paraffin or cetylalcohol). The suspensions may also contain one or more preservatives(e.g., acetic acid, methyl or n-propyl p-hydroxy-benzoate); one or morecoloring agents; one or more flavoring agents; and one or moresweetening agents such as sucrose or saccharin.

The pharmaceutical compositions may also be in the form of oil-in wateremulsions. The oily phase may be a vegetable oil, such as olive oil orarachis oil, a mineral oil, such as liquid paraffin, or a mixture ofthese. Suitable emulsifying agents include naturally-occurring gums,such as gum acacia and gum tragacanth; naturally occurring phosphatides,such as soybean lecithin, esters or partial esters derived from fattyacids; hexitol anhydrides, such as sorbitan monooleate; and condensationproducts of these partial esters with ethylene oxide, such aspolyoxyethylene sorbitan monooleate. The emulsion may also containsweetening and flavoring agents. Syrups and elixirs may be formulatedwith sweetening agents, such as glycerol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, a flavoringor a coloring agent.

Additionally, the pharmaceutical compositions may be in the form of asterile injectable preparation, such as a sterile injectable aqueousemulsion or oleaginous suspension. This emulsion or suspension may beformulated by a person of ordinary skill in the art using those suitabledispersing or wetting agents and suspending agents, including thosementioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, such as a solution in 1,2-propane-diol.

The sterile injectable preparation may also be prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution, and isotonic sodium chloride solution. Inaddition, sterile fixed oils may be employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids (e.g., oleicacid) may likewise be used in the preparation of injectables.

To obtain a stable water-soluble dose form of a pharmaceuticalcomposition, a pharmaceutically acceptable salt of a compound describedherein may be dissolved in an aqueous solution of an organic orinorganic acid, such as 0.3 M solution of succinic acid, or morepreferably, citric acid. If a soluble salt form is not available, thecompound may be dissolved in a suitable co-solvent or combination ofco-solvents. Examples of suitable co-solvents include alcohol, propyleneglycol, polyethylene glycol 300, polysorbate 80, glycerin and the likein concentrations ranging from about 0 to about 60% of the total volume.In one embodiment, the active compound is dissolved in DMSO and dilutedwith water.

The pharmaceutical composition may also be in the form of a solution ofa salt form of the active ingredient in an appropriate aqueous vehicle,such as water or isotonic saline or dextrose solution. Also contemplatedare compounds which have been modified by substitutions or additions ofchemical or biochemical moieties which make them more suitable fordelivery (e.g., increase solubility, bioactivity, palatability, decreaseadverse reactions, etc.), for example by esterification, glycosylation,PEGylation, etc.

In a preferred embodiment, the compounds described herein may beformulated for oral administration in a lipid-based formulation suitablefor low solubility compounds. Lipid-based formulations can generallyenhance the oral bioavailability of such compounds.

As such, a preferred pharmaceutical composition comprises atherapeutically or prophylactically effective amount of a compounddescribed herein, together with at least one pharmaceutically acceptableexcipient selected from the group consisting of medium chain fatty acidsand propylene glycol esters thereof (e.g., propylene glycol esters ofedible fatty acids, such as caprylic and capric fatty acids) andpharmaceutically acceptable surfactants, such as polyoxyl 40hydrogenated castor oil.

In an alternative preferred embodiment, cyclodextrins may be added asaqueous solubility enhancers. Preferred cyclodextrins includehydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosylderivatives of α-, β-, and γ-cyclodextrin. A particularly preferredcyclodextrin solubility enhancer is hydroxypropyl-o-cyclodextrin (BPBC),which may be added to any of the above-described compositions to furtherimprove the aqueous solubility characteristics of the compounds of theembodiments. In one embodiment, the composition comprises about 0.1% toabout 20% hydroxypropyl-o-cyclodextrin, more preferably about 1% toabout 15% hydroxypropyl-o-cyclodextrin, and even more preferably fromabout 2.5% to about 10% hydroxypropyl-o-cyclodextrin. The amount ofsolubility enhancer employed will depend on the amount of the compoundof the invention in the composition.

A pharmaceutical composition contains a total amount of the activeingredient(s) sufficient to achieve an intended therapeutic effect. Morespecifically, in some embodiments, the pharmaceutical compositioncontains a therapeutically effective amount (e.g., an amount of anSAPK-modulating compound that is effective in the prevention ortreatment of the symptoms of an inflammatory disease or condition,wherein the compound exhibits an IC₅₀ in the range of about 0.1 μM toabout 1000 μM, and preferably about 1 μM to about 800 μM, about 1 μM toabout 500 μM, about 1 μM to about 300 μM, about 1 μM to about 200 μM, orabout 1 μM to about 100 μM for inhibition of p38 MAPK). The totalamounts of the compound that may be combined with the carrier materialsto produce a unitary dosing form will vary depending upon the hosttreated and the particular mode of administration. Preferably, thecompositions are formulated so that a dose of between 0.01 to 100 mg/kgbody weight/day of an SAPK-modulating compound is administered to apatient receiving the compositions.

EXAMPLES Synthesis of Compounds of Formula (I)

The following examples show the synthesis of specific compounds ofFormula I, as depicted in Table 1, above.

Synthesis of Compound 1

Following general procedure A, compound 1 was prepared in 50% yield asan oil. MS-ESI: m/z=200.3 [M+1]⁺

Synthesis of Compound 2

Following general procedure A, compound 2 was prepared in 73% yield asan oil. MS-ESI: m/z=200.3 [M+1]⁺

Synthesis of Compound 3

Following general procedure A, compound 3 was prepared in 78% yield asan oil. MS-ESI: m/z=200.3 [M+1]⁺

Synthesis of Compound 4

Following general procedure A, compound 4 was prepared in 46% yield asan oil. MS-ESI: m/z=214.3 [M+1]⁺

Synthesis of Compound 5

Following general procedure A, compound 5 was prepared in 52% yield as ayellowish oil. MS-ESI: m/z=214.3 [M+1]⁺

Synthesis of Compound 6

Following general procedure A, compound 6 was prepared in 86% yield as asolid. MS-ESI: m/z=214.3 [M+1]⁺

Synthesis of Compound 7

Following general procedure A, compound 7 was prepared in 50% yield as awhite solid. MS-ESI: m/z=242.2 [M+1]⁺

Synthesis of Compound 8

Following general procedure A, compound 8 was prepared in 52% yield asan oil. MS-ESI: m/z=212.2 [M+1]⁺

Synthesis of Compound 9

Following general procedure A, compound 9 was prepared in 79% yield asan oil. MS-ESI: m/z=212.3 [M+1]⁺

Synthesis of Compound 10

Following general procedure A, compound 10 was prepared in 48% yield asa white solid. MS-ESI: m/z=212.3 [M+1]⁺

Synthesis of Compound 11

Following general procedure A, compound 11 was prepared in 73% yield asan oil. MS-ESI: m/z=229.2 [M+1]⁺

Synthesis of Compound 12

Following general procedure A, compound 12 was prepared in 81% yield asa white solid. MS-ESI: m/z=229.2 [M+1]⁺

Synthesis of Compound 13

Following general procedure A, compound 13 was prepared in 5.5% yield asa white solid. MS-ESI: m/z=262.3 [M+1]⁺

Synthesis of Compound 14

Following general procedure A, compound 14 was prepared in 35% yield asa white solid. MS-ESI: m/z=262.3 [M+1]⁺

Synthesis of Compound 15

Following general procedure A, compound 15 was prepared in 49% yield asa white solid. MS-ESI: m/z=262.3 [M+1]⁺

Synthesis of Compound 16

Following general procedure A, compound 16 was prepared in 75% yield asa solid. MS-ESI: m/z=268.3 [M+1]⁺

Synthesis of Compound 17

Following general procedure A, compound 17 was prepared in 40% yield asa yellowish solid. MS-ESI: m/z=232.2 [M+1]⁺

Synthesis of Compound 18

Following general procedure A, compound 18 was prepared in 79% yield asan oil. MS-ESI: m/z=232.2 [M+1]⁺

Synthesis of Compound 19

Following general procedure A, compound 19 was prepared in 85% yield asa white solid. MS-ESI: m/z=232.2 [M+1]⁺

Synthesis of Compound 20

Following general procedure A, compound 20 was prepared in 8% yield asan oil. MS-ESI: m/z=254.1 [M+1]⁺

Synthesis of Compound 21

Following general procedure A, compound 21 was prepared in 62% yield asa white solid. MS-ESI: m/z=254.2 [M+1]⁺

Synthesis of Compound 22

Following general procedure A, compound 22 was prepared in 57% yield asa white solid. MS-ESI: m/z=254.3 [M+1]⁺

Synthesis of Compound 23

Following general procedure A, compound 23 was prepared in 30% yield asa white solid. MS-ESI: m/z=278.3 [M+1]⁺

Synthesis of Compound 24

Following general procedure A, compound 24 was prepared in 93% yield asa white solid. MS-ESI: m/z=278.3 [M+1]⁺

Synthesis of Compound 25

Following general procedure A, compound 25 was prepared in 17% yield asa yellowish solid. MS-ESI: m/z=292.2 [M+1]⁺

Synthesis of Compound 26

Following general procedure A, compound 26 was prepared in 50% yield asan oil. MS-ESI: m/z=292.2 [M+1]⁺

Synthesis of Compound 27

Following general procedure A, compound 27 was prepared in 73.5% yieldas a white solid. MS-ESI: m/z=292.2 [M+1]⁺

Synthesis of Compound 28

Following general procedure A, compound 28 was prepared in 4.5% yield asa white solid. MS-ESI: m/z=230.1 [M+1]⁺

Synthesis of Compound 29

Following general procedure A, compound 29 was prepared in 25% yield asan oil. MS-ESI: m/z=230.1 [M+1]⁺

Synthesis of Compound 30

Following general procedure A, compound 30 was prepared in 25% yield asan oil. MS-ESI: m/z=230.2 [M+1]⁺

Synthesis of Compound 31

Following general procedure A, compound 31 was prepared in 52% yield asa white solid. MS-ESI: m/z=260.1 [M+1]⁺

Synthesis of Compound 32

Following general procedure A, compound 32 was prepared in 23.8% yieldas a solid, using triethylamine as a base, instead of pyridine. MS-ESI:m/z=241.2 [M+1]⁺

Synthesis of Compound 33

Following general procedure A, compound 33 was prepared in 81% yield asa white solid. MS-ESI: m/z=211.2 [M+1]⁺

Synthesis of Compound 34

Following general procedure A, compound 34 was prepared in 80% yield asa reddish solid, after crystallization. MS-ESI: m/z=244.4 [M+1]⁺

Synthesis of Compound 35

Following general procedure A, compound 35 was prepared in 82% yield asa yellowish solid. MS-ESI: m/z=230.4 [M+1]⁺

Synthesis of Compound 36

Following general procedure A, compound 36 was prepared in 71% yield asa solid. MS-ESI: m/z=244.2 [M+1]⁺

Synthesis of Compound 37

Following general procedure A, compound 37 was prepared in 72% yield asa white solid. MS-ESI: m/z=228.0 [M+1]⁺

Synthesis of Compound 38

Following general procedure A, compound 38 was prepared in 75% yield asa white solid. MS-ESI: m/z=227.9 [M+1]⁺

Synthesis of Compound 39

Following general procedure A, compound 39 was prepared in 38% yield asa white solid. MS-ESI: m/z=242.9 [M+1]⁺

Synthesis of Compound 40

Following general procedure A, compound 40 was prepared in 81% yield asa white solid. MS-ESI: m/z=188.0 [M+1]⁺¹

Synthesis of Compound 41

Following general procedure A, compound 41 was prepared in 85% yield asa white solid. MS-ESI: m/z=308.2 [M+1]⁺

Synthesis of Compound 42

Following general procedure A, compound 42 was prepared in 91% yield asa white solid. MS-ESI: m/z=308.2 [M+1]⁺

Synthesis of Compound 43

Following general procedure A, compound 43 was prepared in 70% yield asa solid. MS-ESI: m/z=286.1 [M+1]⁺

Synthesis of Compound 44

Following general procedure A, compound 44 was prepared in 23.8% yieldas a white solid. MS-ESI: m/z=241.2 [M+1]⁺

Synthesis of Compound 45

Following general procedure A, compound 45 was prepared in 80% yield asa solid. MS-ESI: m/z=197.3 [M+1]⁺

Synthesis of Compound 46

A solution of 1 (134 mg, 1 mmol), EtSNa (168 mg, 2 mmol) in DMF (5 ml)was heated to 60° C. for 4 h. To the reaction mixture was added HCl(aq.) until pH was about 6. The mixture was evaporated in vacuo to give2. (110 mg, 92%). Pyridine (140 mg, 1.8 mmol) was slowly added to amixture of 2 (110 mg, 0.9 mmol), phenylboronic acid (220 mg, 1.8 mmol)and Cu(OAc)₂ (18 mg) in DCM (5 mL). After the suspension was stirredovernight at room temperature, it was monitored by TLC. When no startingmaterial was detected, the mixture was washed with saturated NaHCO₃. Theorganic layer was dried over sodium sulfate, evaporated in vacuo toafford the crude product, which was purified by preparative TLC to givecompound 46 (50 mg, 25% yield) as a white solid. MS-ESI: m/z=197.3[M+1]⁺

Synthesis of Compound 47

Following general procedure A, compound 47 was prepared in 65% yield asa white solid. MS-ESI: m/z=251.2 [M+1]⁺, 253.2 [M+1]⁺¹

Synthesis of Compound 48

Following general procedure A, compound 48 was prepared in 23% yield asa solid. MS-ESI: m/z=189.2 [M+1]⁺

Synthesis of Compound 49

Following general procedure A, compound 49 was prepared in 1% yield as asolid. MS-ESI: m/z=189.2 [M+1]⁺

Synthesis of Compound 50

Following general procedure A, compound 50 was prepared in 2% yield as awhite solid. MS-ESI: m/z=203.2 [M+1]⁺

Synthesis of Compound 51

Following general procedure B, compound 51 was prepared in 34% yield asa white solid. MS-ESI: m/z=241.2 [M+1]⁺

Synthesis of Compound 52

Following general procedure B, compound 52 was prepared in 22% yield asa white solid. MS-ESI: m/z=241.2 [M+1]⁺

Synthesis of Compound 53

A mixture of 3-Bromo-1H-pyridin-2-one (150 mg, 0.6 mmol)), thienylboromic acid (160 mg, 1.25 mmol)), Pd(PPh₃)₂Cl₂ (30 mg, 0.07 mmol) andNa₂CO₃ (200 mg, 1.88 mmol) in toluene (20 mL) and water (5 mL) washeated at 60° C. overnight under nitrogen atmosphere. Then, water (20mL) was added and the aqueous layer was extracted with CH₂Cl₂ (30 mL×2).The organics were washed by water and brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by prep-TLC to givecompound 52 (85 mg, 56% yields) as a yellowish solid. MS-ESI: m/z=254.3[M+1]⁺

Synthesis of Compound 54

Following general procedure A, compound 54 was prepared in 78% yield asa white solid. MS-ESI: m/z=278.1 [M+1]⁺

Synthesis of Compound 55

Following general procedure D, compound 55 was prepared in 65% yield asa solid. MS-ESI: m/z=274.3 [M+1]⁺

Synthesis of Compound 56

Following general procedure D, compound 56 was prepared in 60% yield asa solid. MS-ESI: m/z=254.3 [M+1]⁺

Synthesis of Compound 57

Following general procedure E, compound 57 was synthesized (yield offirst step 51%; yield of second step 17%). MS-ESI: m/z=274.3 [M+1]⁺

Synthesis of Compound 58

Following general procedure E, compound 58 was prepared in 61% yield asa solid. MS-ESI: m/z=254.3 [M+1]⁺

Synthesis of Compound 59

A mixture of 2,6-dibromopyridine (1) (4 g, 17 mmol), potassiumt-butoxide (20 g, 0.27 mol), and redistilled t-butyl alcohol (100 mL)was refluxed overnight. After cooling, the solvent was removed in vacuo,ice/water was carefully added, and the aqueous layer was extracted withchloroform (100 mL×2), which removed the unreacted staring material. Theaqueous layer was acidified with 3 N HCl, extracted with chloroform (100mL×2), washed with brine, dried over anhydrous Na₂SO₄ and concentratedaffording pure 6-bromo-2-pyridone (2.5 g, 85% yields) as a white solid.The preparation of 3 followed the general procedure A, in a 73% yield. 3was then subjected to the conditions of general procedure A to preparecompound 59 in 35% yield as a yellowish oil. MS-ESI: m/z=274.3 [M+1]⁺

Synthesis of Compound 60

Compound 60 is synthesized in a similar fashion as compound 59, in 7.9%yield as a yellowish oil. MS-ESI: m/z=254.2 [M+1]⁺

Synthesis of Compound 61

To a solution of ethyl vinyl ether (1, 40 mL) in 100 ml ofdichloromethane, pyridine (36 mL) was added. Then a solution oftrifluoroacetic anhydride (87.6 g) in 50 mL of dichloromethane was addedat 0° C. After stirring at room temperature for 30 min, the solution waspoured into 40 mL of H₂O. The layers were separated and the aqueouslayer was extracted again with 40 mL of dichloromethane. The organiclayers were combined, washed with H₂O and dried over MgSO₄. Removal ofsolvent the gave crude 3, which was used directly in the next step.

Trimethylchlorosilane (26.5 mL, 150 mmol) was added to the solution ofzinc powder (10 g, 150 mmol) in anhydrous THF (150 ml) under N₂. Afterstirring for 0.5 h, a solution of chloroacetonitrile (6.35 mL, 100 mmol)and trifluoroacetylvinyl ether (8.4 g, 50 mmol) in anhydrous THF (75 mL)was added dropwise slowly to keep the temperature at 40° C. The mixturewas refluxed for 2 h. After cooling to room temperature, concentratedHCl (25 mL) was added. The mixture was refluxed for 1 h, then cooled toroom temperature. The reaction mixture was then poured into ice water.The product was extracted with EA, and washed with brine. The organiclayer was dried over anhydrous Na₂SO₄, filtered and evaporated todryness to give the residue. The residue was purified by columnchromatography to afford 8.3 g of 5.

Following general procedure A, compound 61 was prepared in 52% yield asa white solid. MS-ESI: m/z=284.0 [M+1]⁺

Synthesis of Compound 62

Following general procedure outlined for compound 61, compound 62 wasprepared in 80% yield as a solid. MS-ESI: m/z=283.0 [M+1]⁺

Synthesis of Compound 63

Following general procedure outlined for compound 61, compound 63 wasprepared in 78% yield as a white solid. MS-ESI: m/z=307.9 [M+1]⁺

Synthesis of Compound 64

Following general procedure F, compound 64 was prepared in 79% for thefirst step and 65% for the second step, to produce an oil. MS-ESI:m/z=290.1 [M+1]⁺

Synthesis of Compound 65

Following general procedure F, compound 65 was prepared in 64% for thefirst step and 60% for the second step, to produce a yellowish solid.MS-ESI: m/z=290.2 [M+1]⁺

Synthesis of Compound 66

Following general procedure F, compound 66 was prepared in 80% for thefirst step and 56% for the second step. MS-ESI: m/z=250.2 [M+1]⁺

Synthesis of Compound 67

Following general procedure F, compound 67 was prepared in 85% for thefirst step. The second step was performed at 0° C., using DCM as thesolvent, giving compound 67 in 76% yield for the second step. MS-ESI:m/z=268.2 [M+1]⁺

Synthesis of Compound 68

Following general procedure F, compound 68 was prepared in 10% for thefirst step and 15% for the second step to give a white solid. MS-ESI:m/z=222.7 [M+1]⁺

Synthesis of Compound 69

Following general procedure F, compound 69 was prepared in 79% for thefirst step and 59% for the second step. MS-ESI: m/z=222.7 [M+1]⁺

Synthesis of Compound 70

Following general procedure F, compound 70 was prepared in 75% for thefirst step and 63% for the second step. MS-ESI: m/z=223.2 [M+1]⁺

Synthesis of Compound 71

Following general procedure F, compound 71 was prepared in 85% for thefirst step. The second step was carried out at room temperature in acapped plastic tube for 6 hours to give an oil in a 50% yield for thesecond step. MS-ESI: m/z=265.2 [M+1]⁺

Synthesis of Compound 72

Following general procedure F, compound 72 was prepared in 89% for thefirst step and 53% for the second step, where in the second step, 4 eqof DAST was used. MS-ESI: m/z=272.0 [M+1]⁺

Synthesis of Compound 73

Following general procedure F, compound 73 was prepared in 89% for thefirst step and 58% for the second step to give an oil, where in thesecond step, 4 eq of DAST was used. MS-ESI: m/z=272.0 [M+1]⁺

Synthesis of Compound 74

Following general procedure F, compound 74 was prepared in 85% for thefirst step and 56% for the second step to give an oil, where in thesecond step, 6 eq of DAST was used. MS-ESI: m/z=286.0 [M+1]⁺

Synthesis of Compound 75

Following general procedure F, compound 75 was prepared in 71.4% for thefirst step and 39% for the second step to give a white solid, where inthe second step, 6 eq of DAST was used. MS-ESI: m/z=286.0 [M+1]⁺

Synthesis of Compound 76

Following general procedure F, compound 76 was prepared in 89% for thefirst step and 57% for the second step to give a white solid. MS-ESI:m/z=290.0 [M+1]⁺

Synthesis of Compound 77

Following general procedure G, compound 77 was prepared in 20% yield asa white solid. MS-ESI: m/z=291.9 [M+1]⁺

Synthesis of Compound 78

Following general procedure G, compound 78 was prepared in 38% yield asa white solid. MS-ESI: m/z=291.0 [M+1]⁺

Synthesis of Compound 79

Following general procedure G, compound 79 was prepared in 78% yield asa white solid. MS-ESI: m/z=315.9 [M+1]⁺

Synthesis of Compound 80

Following general procedure G, compound 80 was prepared in 83% yield asa solid. MS-ESI: m/z=290.0 [M+1]⁺

Synthesis of Compound 81

Following general procedure G, compound 81 was prepared in 85% yield asa solid. MS-ESI: m/z=290.0 [M+1]⁺

Synthesis of Compound 82

Following general procedure G, compound 82 was prepared in 70% yield asa white solid. MS-ESI: m/z=304.9 [M+1]⁺

Synthesis of Compound 83

Following general procedures G then F, compound 83 was prepared in 90%for first step and 25% yield for second step (fluorination) as ayellowish oil. MS-ESI: m/z=298 [M+1]⁺

Synthesis of Compound 84

Following general procedures G then F, compound 84 was prepared in 83%for first step and 54% yield for second step (fluorination). MS-ESI:m/z=298.4 [M+1]⁺

Synthesis of Compound 85

Following general procedures G then F, compound 85 was prepared in 86%for first step and 49% yield for second step (fluorination). MS-ESI:m/z=312.0 [M+1]⁺

Synthesis of Compound 86

Following general procedures G then F, compound 86 was prepared in 82%for first step and 56% yield for second step (fluorination). MS-ESI:m/z=312.0 [M+1]⁺

Synthesis of Compound 87

Following general procedures A then F, compound 87 was synthesized in86% yield then 20% yield for the second step (fluorination). MS-ESI:m/z=236 [M+1]⁺

Synthesis of Compound 88

Following general procedures A then F, compound 88 was synthesized in65% yield then 25% yield for the second step (fluorination). MS-ESI:m/z=236 [M+1]⁺

Synthesis of Compound 89

Following general procedures A then F, compound 89 was synthesized in72% yield then 26% yield for the second step (fluorination). MS-ESI:m/z=250.0 [M+1]⁺

Synthesis of Compound 90

Following general procedures A then F, compound 90 was synthesized in75% yield then 27% yield for the second step (fluorination). MS-ESI:m/z=250.0 [M+1]⁺

Synthesis of Compound 91

3, above, was prepared using general procedure A. 4 was prepared in thefollowing manner. To a solution of 3 (1 eq) in tetrahydrofuran-methanol(10:1) was added sodium borohydride (5 eq) at 0° C. The mixture wasstirred at room temperature for 30 min. Water was added and then mixturewas extracted with EA. The organics were washed with brine, dried overNa₂SO₄ and concentrated in vacuo. 4 was isolated by prep-TLC. 5 wasprepared according to general procedure F. Compound 91 was preparedunder these reaction conditions to provide 86% yield of first step, 70%yield of second step, and 30% yield of third step. MS-ESI: m/z=272.2[M+1]⁺

Synthesis of Compound 92

Similar to synthesis of compound 91, compound 92 was prepared to provide82% yield of first step, 85% yield of second step, and 15% yield ofthird step. MS-ESI: m/z=272.3 [M+1]⁺

Synthesis of Compound 93

Similar to synthesis of compound 91, compound 93 was prepared to provide80% yield of first step, 79.5% yield of second step, and 50% yield ofthird step. MS-ESI: m/z=232.3 [M+1]⁺

Synthesis of Compound 94

Similar to synthesis of compound 91, compound 94 was prepared to provide82.9% yield of first step, 51% yield of second step, and 32% yield ofthird step. MS-ESI: m/z=250.2 [M+1]⁺

Synthesis of Compound 95

To a solution of 5-bromo-2-methoxy-pyridine (2.4 g, 8.94 mmol),(E)-prop-1-enylboronic acid (1 g, 11.6 mmol), K₃PO₄ (6.6 g, 31.3 mmol)and tricyclohexylphosphine (250 mg, 0.894 mmol) in toluene (40 mL) andwater (2 mL) under a nitrogen atmosphere was added palladium acetate(100 mg, 0.447 mmol). The mixture was heated to 100° C. for 3 h and thencooled to room temperature. Water (100 mL) was added and the mixtureextracted with EA (2×150 mL), the combined organics were washed withbrine (100 mL), dried over Na₂SO₄ and concentrated in vacuo. The productwas purified by column chromatography to give 1.3 g of compound 3(68.4%, yield). Compound 3 (1.3 g, 8.72 mmol) was added to a stirredsolution of hydrobromic acid (9.7 mL) in absolute ethanol (234 mL) undernitrogen and the mixture was heated under reflux for 5 hours. The cooledsolution was evaporated in vacuo, and the residue partitioned between10% sodium carbonate solution and DCM. The organic phase was dried withNa₂SO₄ and evaporated in vacuo to give 1.04 g of compound 4 as a whitesolid. (89% yield). Compound 5 was prepared using general procedure A.Compound 95 was prepared to give 85% yield of an oil. MS-ESI: m/z=255.3[M+1]⁺

Synthesis of Compound 96

Similar to synthesis of compound 95, compound 96 was prepared to provide89% yield as a white solid. MS-ESI: m/z=280.2 [M+1]⁺

Synthesis of Compound 97

Using the procedure as outlined for compound 95 and general procedure F,compound 97 was prepared in 82% yield (first step) and 59% yield (secondstep). MS-ESI: m/z=262.2 [M+1]⁺

Synthesis of Compound 98

Meta-chloroperbenzoic acid (mCPBA, 5 eq.) was added to the solution of 1in DCM at −78° C. The reaction was stirred at 0° C. for 20 minutes, thenfiltered. The reaction filtrate was purified by prep-TLC to give 2.Following this general procedure, compound 18 was subjected to theseconditions to provide compound 98 in 22% yield as a white solid. MS-ESI:m/z=263.9 [M+1]⁺

Synthesis of Compound 99

Similar to the synthesis of compound 98, compound 99 was prepared fromcompound 19 to provide compound 99 in 40% yield as a yellowish solid.MS-ESI: m/z=264 [M+1]⁺

Synthesis of Compound 100

Similar to the synthesis of compound 98, compound 100 was prepared fromcompound 67 to provide compound 100 in 80% yield as a white solid.MS-ESI: m/z=300.2 [M+1]⁺

Synthesis of Compound 101

2 is prepared using general procedure A in 84% yield. A mixture of 2 (1g, 5 mmol) and trimethyl-trifluoromethyl-silane (3.5 mL, 2M in THF, 7mmol) in THF (20 mL) was cooled to 0° C. in an ice bath and treated withtetrabutylammonium fluoride (0.25 mL, 1 M in THF, 0.25 mmol) undernitrogen atmosphere at 0° C. for 30 min. The mixture was warmed to roomtemperature and stirred 24 h. Then, 1 M HCl (50 mL) was added, and themixture was stirred overnight. The aqueous layer was extracted with EA(50 mL×2) and the organic layer was concentrated. The desired productwas separated by column chromatography to give pure intermediate (0.94g, 70% yield) as yellow solid. MS-ESI: m/z=270.2 [M+1]⁺ The intermediate(50 mg, 0.19 mmol) and manganese dioxide (165 mg, 1.9 mmol) were stirredovernight at room temperature in DCM (5 mL). The progress of thereaction was detected by TLC. Upon completion, the crude mixture wasfiltered through a pad of celite and the filtrate was concentrated.Compound 101 was isolated by washing the crude with petroleum ether togive pure product (36 mg, 70% yields) as a white solid. MS-ESI:m/z=268.2 [M+1]⁺

Synthesis of Compound 102

Following general procedure A, compound 102 was prepared in 80% yield asa white solid. MS-ESI: m/z=268.2 [M+1]⁺

Synthesis of Compound 103

Compound 103 was prepared from compound 102. A mixture of compound 102(2 g, 10 mmol) and trimethyl-trifluoromethyl-silane (7 ml, 2M in THF, 15mmol) in THF (40 mL) was cooled to 0° C. in an ice bath and then treatedwith tetrabutylammonium fluoride (0.5 ml, 1 M in THF, 0.5 mmol) undernitrogen atmosphere at 0° C. for 30 min. The mixture was warmed to roomtemperature and stirred 24 h. Then, 1 M HCl (50 mL) was added and themixture was stirred overnight. The aqueous layer was extracted with EA(70 mL×2) and the organic layer was concentrated. The desired productwas separated by column chromatography to give pure compound 103 (1.5 g,45% yields) as a white solid.

MS-ESI: m/z=338.3 [M+1]⁺

Synthesis of Compound 104

Compound 104 was prepared from compound 103. Potassium bromate (16.6 g,0.1 mol) was added over 0.5 h to a vigorously stirred mixture of2-iodobenzoic acid (20 g, 0.08 mmol) and 180 mL 0.73 M H₂SO₄ (0.13 mol)in a 55° C. bath. The mixture was stirred for 4 h at 68° C., and the Br₂formed was removed by reduced pressure in the reaction process. Thereaction was cooled to room temperature with an ice bath. Filtration andwashing of the solid with ice water and iced ethanol gave the desiredcompound IBX (16 g, 70% yield). Compound 103 (1 g, 3 mmol) was dissolvedin EA (50 mL), and IBX (4 g, 15 mmol) was added. The resultingsuspension was immersed in an oil bath set to 80° C. and stirredvigorously open to the atmosphere overnight. The reaction was cooled toroom temperature and filtered. The filter cake was washed with EA, andthe combined filtrates were concentrated. The desired compound wasobtained (0.98 g, 98% yields) as a white solid. MS-ESI: m/z=336 [M+1]⁺

Synthesis of Compound 105

Compound 105 was prepared from compound 104. Compound 104 (80 mg, 0.24mmol) in dry DCM (1.5 mL) was added at the temperature of −78° C. underN₂ atmosphere to a solution of DAST (50 mg, 0.31 mmol) in DCM (0.5 mL).The mixture was stirred at −78° C. for 2 h, and then warmed to roomtemperature overnight. The reaction mixture was diluted with DCM (20mL), and poured into saturated NaHCO₃ (30 mL). The organic phase wasseparated and dried over Na₂SO₄ and concentrated in vacuo. Compound 105was isolated by thin-layer chromatography (42 mg, 50% yields) as a whitesolid. MS-ESI: m/z=340.2 [M+1]⁺

Synthesis of Compound 106

Compound 106 was prepared from compound 104. Compound 104 (100 mg, 0.3mmol) was dissolved in acetonitrile (1.2 mL), and DAST (100 mg, 0.6mmol) was added. Fluorination was carried out at 80° C. in a pressurevessel for 4 h. After cooling to room temperature, the reaction mixturewas diluted with DCM (20 mL), and poured into the saturated sodiumbicarbonate solution (30 mL). The organic phase was separated and driedover sodium sulfate. Compound 106 was isolated by prep-TLC (20 mg, 20%yields) as a yellowish solid. MS-ESI: m/z=357.7 [M+1]⁺

Synthesis of Compound 107

Compound 107 was prepared from compound 104.

A mixture of Compound 104 (80 mg, 0.24 mmol) andtrimethyl-trifluoromethyl-silane (0.07 mL pure, 0.49 mmol) in THF (2.5mL) cooled to 0° C. in an ice bath is treated with tetrabutylammoniumfluoride (0.5 mL, 0.024 M in THF, 0.012 mmol) under nitrogen atmosphereat 0° C. for 30 min. The mixture was raised to room temperature andstirred 24 h. Then, 1 M HCl (20 mL) was added and the mixture wasstirred overnight. The aqueous layer was extracted with EA (30 mL×2) andthe organic layers were concentrated. The desired product was separatedout by washing the crude with EA to give Compound 107 (50 mg, 52% yield)as a yellowish solid. MS-ESI: m/z=406.2 [M+1]⁺

Synthesis of Compound 108

A slurry of pyrimidin-2(1H)-one (1 g, 10.4 mmol), triphenylbismuth (6.88g, 15.6 mmol), anhydrous Cu(OAc)₂ (2.84 g, 15.6 mmol) and NEt₃ (2.5 mL)in anhydrous DCM (16 mL) was stirred at room temperature under anitrogen atmosphere. After a period of two days, the solution becamegelatinous and changed from deep blue to light green. The reactionmixture was diluted with DCM then filtered. The filtrate was washed withNaHCO₃, EDTA and NaCl (aq) and then dried with Na₂SO₄. Compound 108 wasisolated by flash column chromatography (358 mg, 20% yield). MS-ESI:m/z=173.2 [M+1]⁺

Synthesis of Compounds 109 & 110

Compound 109 was prepared from compound 108. Sodium borohydride (200 mg5.26 mmol) was added slowly to a solution of Compound 108 (90 mg, 0.526mmol) in acetic acid (32 mL) and the mixture was stirred for 30 min atroom temperature. The reaction mixture was neutralized cautiously withaqueous sodium hydroxide, on an ice-water bath, and then extracted withdichloromethane and dried over anhydrous magnesium sulfate. Compound 109(78 mg, 39%, MS-ESI: m/z=173.2 [M+1]⁺) and Compound 110 (59 mg, 29%,MS-ESI: m/z=177.2 [M+1]⁺) were obtained by prep-TLC.

Synthesis of Compound 111

Following general procedure A, compound 112 was prepared in 45% yield asa white solid. MS-ESI: m/z=242.2 [M+1]⁺

Synthesis of Compound 112

Following general procedure A, compound 113 was prepared in 72% yield asan oil. MS-ESI: m/z=230.2 [M+1]⁺

Synthesis of Compound 113

Following general procedure A, compound 114 was prepared in 75% yield asa solid. MS-ESI: m/z=268.2 [M+1]⁺

Synthesis of Compound 114

Following General procedure H2, compound 114 was synthesized in 20%yield. ‘1H NMR (300 MHz, DMSO-d₆) ppm 7.68 (dd, 1H), 7.45-7.61 (m, 5H),6.50 (dd, 1H), 6.33 (td, 1H)

Synthesis of Compound 115

A for compound 115 was prepared in the following manner. A solution of5-cyano-2-methoxy pyridine (1 eq), sodium ethylsulfide (EtSNa) (2 eq) inDMF (5 ml/eq) was heated to 60° C. for 4 h. To the reaction mixture wasadded HCl-Et₂O until the mixture reached a pH of about 6, under nitrogenflush, in order to remove volatiles (Et2O and EtSH). The mixture wascentrifuged and filtered, which removed the sodium chloride. The DMFsolution was used as prepared in General procedure H2 to providecompound 115 in 21% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.63 (d, 1H),7.77 (dd, 1H), 7.64 (m, 2H), 7.55 (m, 2H), 6.61 (d, 1H)

Synthesis of Compound 116

For compound 116, A was prepared according to general procedure I, asfollows.

The 5-bromo-2-methoxy-pyridine (750 mg, 4 mmol), cyclopropyl boronicacid (1.08 g, 12.5 mmol) KF (760 mg, 13 mmol) and Pd(PPh₃)₄ weredissolved in toluene (12 ml) and the reaction mixture was heated at 150°C. by microwave for 1.5 h. The crude was purified by columnchromatography to give the intermediate (1.33 g 74% yield) as colorlessoil. To a magnetically stirred solution of5-cyclopropyl-2-methoxy-pyridine (1.33 g, 8.9 mmol), in 30 mL of DMF,EtSNa (1.502 g, 17.8 mmol) was added. The mixture was heated at 90° C.for 24 h. The reaction was cooled at room temperature and HCl/Et₂O wasadded until pH 6. EtSH formed. The remaining HCl/Et₂O and EtSH wasevaporated by bubbling N₂ at 40° C. The solution of A (concentration 40mg/ml) was use as such for the next step. Following general procedureH1A, compound 116 was prepared in 25% yield. ¹H NMR (300 MHz, DMSO-d6)ppm 8.65-8.77 (m, 2H), 7.51-7.57 (m, 2H), 7.48 (d, 1H), 7.30 (dd, 1H),6.46 (d, 1H), 1.69-1.85 (m, 1H), 0.76-0.87 (m, 2H), 0.57-0.66 (m, 2H)

Synthesis of Compound 117

Compound A for compound 117 was prepared as stated for compound 116. Theprepared compound A was used in General procedure H1A to providecompound 117 in 25% yield. ¹H NMR (300 MHz, DMSO-d₆) ppm 10.10 (s, 1H),7.65 (t, 1H), 7.51-7.61 (m, 1H), 7.36-7.45 (m, 2H), 7.25 (dd, 1H), 7.04(ddd, 1H), 6.41 (d, 1H), 2.06 (s, 3H), 1.67-1.84 (m, 1H), 0.73-0.87 (m,2H), 0.52-0.63 (m, 2H)

Synthesis of Compound 118

Compound A for compound 118 was prepared as stated for compound 116. Theprepared compound A was used in General procedure H1A to providecompound 118 in 18% yield. ¹H NMR (300 MHz, DMSO-d₆) ppm 7.56 (m, 2H),7.49 (m, 2H), 7.46 (d, 1H), 7.28 (dd, 1H), 6.44 (d, 1H), 1.67-1.84 (m,1H), 0.73-0.89 (m, 2H), 0.54-0.65 (m, 2H)

Synthesis of Compound 119

Following General procedure H2, compound 119 was synthesized in 45%yield. ‘1H NMR (300 MHz, DMSO-d₆) ppm 7.63 (ddd, 1H), 7.31-7.58 (m, 6H),6.40-6.55 (m, 1H), 6.31 (td, 1H)

Synthesis of Compound 120

Following General procedure H2, compound 120 was synthesized in 30%yield. ‘1H NMR (300 MHz, DMSO-d₆) ppm 8.03 (dd, 1H), 7.73 (dd, 1H),7.45-7.60 (m, 5H), 6.63 (dd, 1H), 2.71 (s, 6H)

Synthesis of Compound 121

Following General procedure I, A was prepared as follows.

The 5-Furan-2-yl-1H-pyridin-2-one product was obtained by reaction of2.66 g (14 mmol) of 5-bromo-2-methoxy-pyridine. After purification(SiO₂; Pet. Ether/AcOEt 9:1) 1.83 g (75% yield) of pure product wereobtained as white solid. The obtained product was de-methylated usingEtSNa. The obtained A in a DMF solution (10 mmol/30 ml) was used for theChan Lam reaction, following General Procedure H2 to provide compound121 in 19% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.85-7.94 (m, 2H), 7.66(dd, 1H), 7.42-7.59 (m, 5H), 6.80 (dd, 1H), 6.60 (dd, 1H), 6.55 (dd, 1H)

Synthesis of Compound 122

Following General procedure H1A, compound 122 was synthesized in 53%yield. ¹H NMR (300 MHz, DMSO-d₆) ppm 10.13 (s, 1H), 7.69 (t, 1H), 7.61(ddd, 1H), 7.54-7.59 (m, 1H), 7.47-7.54 (m, 1H), 7.42 (t, 1H), 7.04(ddd, 1H), 6.39-6.53 (m, 1H), 6.31 (td, 1H), 2.06 (s, 3H)

Synthesis of Compound 123

Following General procedure H1A, compound 123 was synthesized in 37%yield. ¹H NMR (300 MHz, DMSO-d₆) ppm 8.13 (d, 1H), 7.73 (dd, 1H), 7.66(m, 2H), 7.55 (m, 2H), 6.64 (d, 1H), 2.71 (s, 6H)

Synthesis of Compound 124

For compound 124, A was prepared as described for compound 121. Theobtained A in a DMF solution (10 mmol/30 ml) was used for the Chan Lamreaction, following General Procedure H2 to provide compound 124 in 13%yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.98 (d, 1H), 7.90 (dd, 1H),7.66-7.68 (m, 1H), 7.66 (m, 2H), 7.54 (m, 2H), 6.81 (dd, 1H), 6.62 (dd,1H), 6.56 (dd, 1H)

Synthesis of Compound 125

Following General procedure H2, compound 125 was synthesized in 20%yield. ¹H NMR (300 MHz, DMSO-d₆) ppm 10.16 (s, 1H), 8.02 (d, 1H), 7.75(t, 1H), 7.72 (dd, 1H), 7.57-7.66 (m, 1H), 7.46 (t, 1H), 7.15 (ddd, 1H),6.63 (d, 1H), 2.71 (s, 6H), 2.07 (s, 3H)

Synthesis of Compound 126

Following General procedure H2, compound 126 was synthesized in 13%yield. ¹H NMR (300 MHz, DMSO-d₆) ppm 8.73 (dd, 2H), 7.70 (ddd, 1H),7.49-7.60 (m, 3H), 6.52 (ddd, 1H), 6.37 (td, 1H)

Synthesis of Compound 127

Compound A for compound 127 was prepared as stated for compound 115. Theprepared compound A was used in General procedure H2 to provide compound127 in 33% yield. ¹H NMR (300 MHz, DMSO-d₆) ppm 10.15 (s, 1H), 8.58 (d,1H), 7.75 (dd, 1H), 7.72 (t, 1H), 7.60 (ddd, 1H), 7.45 (t, 1H), 7.10(ddd, 1H), 6.59 (dd, 1H), 2.07 (s, 3H)

Synthesis of Compound 128

For compound 128, A was prepared as described for compound 121. Theobtained demethylated A in a DMF solution (10 mmol/30 ml) was used forthe Chan Lam reaction, following General Procedure H2 to providecompound 128 in 20% yield. 1H NMR (300 MHz, DMSO-d6) ppm 10.14 (s, 1H),7.83-7.96 (m, 2H), 7.70-7.77 (m, 1H), 7.66 (dd, 1H), 7.60 (ddd, 1H),7.45 (t, 1H), 7.13 (ddd, 1H), 6.80 (dd, 1H), 6.57-6.64 (m, 1H), 6.55(dd, 1H), 2.07 (s, 3H)

Synthesis of Compound 129

Compound A for compound 129 was prepared as stated for compound 116. Theprepared compound A was used in General procedure H1A to providecompound 129 in 23% yield. ¹H NMR (300 MHz, DMSO-d₆) ppm 7.92 (m, 2H),7.62 (m, 2H), 7.41-7.53 (m, 3H), 7.29 (dd, 1H), 6.45 (d, 1H), 1.68-1.84(m, 1H), 0.74-0.88 (m, 2H), 0.52-0.67 (m, 2H)

Synthesis of Compound 130

Following General procedure I, A was prepared as follows.

Following standard Suzuki coupling, the 2-Methoxy-5-phenyl-pyridine wasobtained by reaction of 1.9 g (10 mmol) of 5-bromo-2-methoxy-pyridine.After purification (SiO₂; Pet. Ether/EA 9:1) 1.8 g (97% yield) of pureproduct were obtained as white solid. The 2-Methoxy-5-phenyl-pyridine (1g, 5.4 mmol) was added to HSO₃C1 (2 ml) at 0° C. The dark solution wasstirred at room temperature for 4 h and then poured onto ice.Concentrated ammonia was added, while maintaining the temperature <10°C. The intermediate was extracted with EA (1.2 g, 84% yield) and usedfor the next step without further purification. To a magneticallystirred solution of the intermediate(4-(6-Methoxy-pyridin-3-yl)-benzenesulfonamide, 1.2 g, 4.5 mmol), in 3mL of EtOH, 15 mL of HBr were added. The mixture was heated at 80° C.for 20 h. The reaction was cooled at room temperature and poured intoKHCO₃ saturated solution. EA was added and the mixture was transferredinto a separator funnel. The aqueous layer was separated and extractedwith additional portion of EA. The combined organics were washed oncewith water. The organic layer was dried with sodium sulfate, filteredand evaporated under vacuum, affording 300 mg of A. The aqueous layerwas acidified and the solvent was evaporated under vacuum. Purificationby flash column chromatography (EA) afforded 750 mg of A (89% of yield).A was used for the Chan Lam reaction, following General Procedure H1A toprovide compound 130 in 77% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.12(d, 1H), 8.00 (dd, 1H), 7.83 (m, 4H), 7.42-7.64 (m, 5H), 7.34 (s, 2H),6.64 (d, 1H)

Synthesis of Compound 131

Compound A for compound 131 was prepared as stated for compound 130. Theprepared compound A was used in General procedure H1A to providecompound 131 in 61% yield. ¹H NMR (300 MHz, DMSO-d₆) ppm 8.18 (d, 1H),8.02 (dd, 1H), 7.84 (m, 4H), 7.69 (m, 2H), 7.55 (m, 2H), 7.34 (s, 2H),6.65 (d, 1H)

Synthesis of Compound 132

Compound A for compound 132 was prepared as stated for compound 116. Theprepared compound A was used in General procedure H1A to providecompound 132 in 25% yield. ¹H NMR (300 MHz, DMSO-d₆) ppm 7.42-7.57 (m,3H), 7.36-7.42 (m, 2H), 7.33 (dd, 1H), 7.13-7.24 (m, 1H), 6.80 (d, 1H),1.66-1.81 (m, 1H), 0.86-0.97 (m, 2H), 0.52-0.64 (m, 2H)

Synthesis of Compound 133

For compound 133, A was prepared as described for compound 121. Theobtained A in a DMF solution (10 mmol/30 ml) was used for the Chan Lamreaction, following General Procedure H2 to provide compound 133 in 17%yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.87-8.96 (m, 2H), 7.79-7.85 (m,2H), 7.69-7.77 (m, 2H), 7.44 (dd, 1H), 6.76-6.84 (m, 1H), 6.47-6.57 (m,2H)

Synthesis of Compound 134

Following General procedure I, A was prepared as follows.

Following standard Suzuki coupling, an intermediate was obtained byreaction of 2.82 g (15 mmol) of 5-bromo-2-methoxy-pyridine. Afterpurification (SiO₂; Pet. Ether/EA 9:1) 2.8 g (92% yield) of pureintermediate were obtained as white solid. The intermediate (900 mg) wasdissolved in HBr 48% (10 ml) and EtOH (3 ml) and the solution was heatedat reflux for 3 h. After evaporation of volatiles the desired A pyridonewas obtained as white solid (780 mg, 93% yield). A was used in the ChanLam reaction, following General Procedure H1A to provide compound 134 in33% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.02 (d, 1H), 7.87-7.99 (m,3H), 7.73 (m, 2H), 7.69 (m, 2H), 7.50 (s, 2H), 7.25 (m, 2H), 6.62 (d,1H)

Synthesis of Compound 135

For compound 135, A was prepared as described for compound 134. A wasused in the Chan Lam reaction, following General Procedure H1A toprovide compound 135 in 59% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 10.13(s, 1H), 7.86-7.96 (m, 2H), 7.74 (t, 1H), 7.55-7.71 (m, 3H), 7.44 (t,1H), 7.23 (m, 2H), 7.14 (ddd, 1H), 6.55-6.64 (m, 1H), 2.06 (s, 3H)

Synthesis of Compound 136

For compound 136, A was prepared as described for compound 134. A wasused in the Chan Lam reaction, following General Procedure H1A toprovide compound 136 in 53% yield. ¹H NMR (300 MHz, DMSO-d₆) ppm 7.94(d, 1H), 7.91 (dd, 1H), 7.68 (m, 2H), 7.40-7.59 (m, 5H), 7.23 (m, 2H),6.60 (dd, 1H)

Synthesis of Compound 137

For compound 137, A was prepared as described for compound 134. A wasused in the Chan Lam reaction, following General Procedure H1A toprovide compound 137 in 53% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.01(d, 1H), 7.93 (dd, 1H), 7.63-7.74 (m, 4H), 7.53 (m, 2H), 7.24 (m, 2H),6.61 (dd, 1H)

Synthesis of Compound 138

For compound 138, A was prepared as follows:

1.53 g (10 mmol) of 2-methoxy-pyridine-5-boronic acid and 2.46 g (15mmol) of 2-Bromo-thiazole and K₂CO₃ (3 eq) were dissolved in a 10:1mixture of DME/H₂O (4 ml/mmol). The solution was degassed by bubbling N₂for 15 min and then Pd(PPh₃)₄ (0.05 eq) was added. The reaction mixturewas heated at 90° C. for 8 h an then cooled at room temperature, dilutedwith EA and filtered on a celite plug. The filtrate was washed withbrine. The separated organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. After purification (SiO₂; Pet.Ether/EA 9:1) 1.8 g (92% yield) of a 1:1 mixture of intermediate and thedimeric 2-methoxy-pyridine were obtained and used for the next step. Themixture (1.1 g) was dissolved in HBr 48% (10 ml) and EtOH (3 ml) and thesolution was heated at reflux for 3 h. After evaporation of volatiles,the crude was purified by column chromatography (SiO₂; Pet. Ether/EA9:1) leading to the desired pyridone A (350 mg). Following generalprocedure H1A, compound 138 was prepared in 35% yield. ¹H NMR (300 MHz,DMSO-d6) ppm 8.23 (d, 1H), 8.07 (dd, 1H), 7.84 (d, 1H), 7.70 (d, 1H),7.41-7.63 (m, 5H), 6.64 (d, 1H)

Synthesis of Compound 139

Following general procedure I, A was prepared as follows.

Following standard procedure for Suzuki coupling, the intermediate wasobtained by reaction of 3 g (16 mmol) of 5-bromo-2-methoxy-pyridine.After purification (SiO₂; Hexane/EA 30/1 to EA) 2.2 g (51% yield) of theintermediate were obtained as white solid. To a magnetically stirredsolution of 2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-pyridine (1.2 g, 6.3mmol), in 3 mL of EtOH, 15 mL of HBr were added. The mixture was heatedat 80° C. for 20 h. The reaction was cooled at room temperature. Thesolvent was evaporated under vacuum. Purification by flash columnchromatography (EA) afforded 1.1 g of A (quantitative yield). Followinggeneral procedure H1A, compound 139 was prepared in 63% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.04 (d, 1H), 7.94 (dd, 1H), 7.79 (d, 1H), 7.79(dd, 1H), 7.62 (m, 2H), 7.54 (m, 2H), 6.56 (d, 1H), 3.82 (s, 3H)

Synthesis of Compound 140

For compound 140, A was prepared as described for compound 134. A wasused in the Chan Lam reaction, following General Procedure H1A toprovide compound 140 in 30% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 9.26(s, 1H), 9.08 (s, 2H), 8.18 (d, 1H), 7.99 (dd, 1H), 7.70 (m, 2H), 7.27(m, 2H), 6.66 (d, 1H)

Synthesis of Compound 141

For compound 141, A was prepared as described for compound 134. A wasused in the Chan Lam reaction, following General Procedure H1A toprovide compound 141 in 45% yield. ¹H NMR (300 MHz, DMSO-d6) ppm8.68-8.81 (m, 2H), 8.02 (dd, 1H), 7.94 (dd, 1H), 7.70 (m, 2H), 7.62-7.66(m, 2H), 7.26 (m, 2H), 6.64 (dd, 1H)

Synthesis of Compound 142

Compound A for compound 142 was prepared according to the followingscheme.

6-Methoxy-pyridin-3-ylamine (2.5 g 2 mmol) was dissolved in 48% HBF₄ (10ml) and cooled at 0° C. NaNO₂ (2.4 g, 3.4 mmol) was added portionwisemaintaining the temperature <5° C. The dark solution was stirred at lowtemperature for 1 h. The solid was collected by filtration and washedwith water and then dried under vacuum. The desired diazonium salt wasobtained (3.18 g, 72%) as white crystalline solid. The diazonium salt (2g, 8.9 mmol) and celite (4 g) were finely mixed in a mortar, transferredto a reaction vessel, then gradually heated to 150° C., whereupon arapid evolution of fumes occurred. The resulting solid was washedseveral times with abundant diethyl ether. The organic solution waswashed with Et₂O/HCl then evaporated to provide the desired intermediateas its hydrochloric salt (1.2 g) as pale yellow viscous oil. Theobtained fluoromethoxy pyridine (1.2 g) was dissolved in HBr 48% (10 ml)and EtOH (3 ml) and the solution was heated at reflux for 6 h. Afterevaporation of volatiles the desired pyridone A was obtained asamorphous solid in quantitative yield, and used in General procedure H1Ato provide compound 142 in 28% yield. ¹H NMR (300 MHz, DMSO-d6) ppm7.85-7.97 (m, 1H), 7.59-7.73 (m, 1H), 7.34-7.57 (m, 5H), 6.45-6.57 (m,1H)

Synthesis of Compound 143

Using A as prepared as described for compound 142, following Generalprocedure H1A, compound 143 was prepared in 13% yield. ¹H NMR (300 MHz,DMSO-d6) ppm 10.13 (br. s., 1H), 7.89 (ddd, 1H), 7.69-7.72 (m, 1H), 7.67(ddd, 1H), 7.57 (ddd, 1H), 7.35-7.48 (m, 1H), 6.97-7.16 (m, 1H), 6.51(ddd, 1H), 2.06 (s, 3H)

Synthesis of Compound 144

Using A as prepared as described for compound 142, following Generalprocedure H1A, compound 144 was prepared in 26% yield. ¹H NMR (300 MHz,DMSO-d6) ppm 10.13 (br. s., 1H), 7.89 (ddd, 1H), 7.69-7.72 (m, 1H), 7.67(ddd, 1H), 7.57 (ddd, 1H), 7.35-7.48 (m, 1H), 6.97-7.16 (m, 1H), 6.51(ddd, 1H), 2.06 (s, 3H)

Synthesis of Compound 145

For compound 145, A was prepared as described for compound 139. A wasused in the Chan Lam reaction, following General Procedure H1A toprovide compound 145 in 42% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.04(s, 1H), 7.88 (dd, 1H), 7.71-7.83 (m, 2H), 7.36-7.61 (m, 5H), 6.54 (dd,1H), 3.82 (s, 3H)

Synthesis of Compound 146

For compound 146, A was prepared as described for compound 121. Theobtained demethylated A in a DMF solution (10 mmol/30 ml) was used forthe Chan Lam reaction, following General Procedure H2 to providecompound 146 in 7% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 9.26 (s, 1H),9.04 (s, 2H), 8.15 (d, 1H), 7.95 (dd, 1H), 7.70 (dd, 1H), 6.81 (dd, 1H),6.67 (dd, 1H), 6.58 (dd, 1H)

Synthesis of Compound 147

Following general procedure I, A was prepared as follows.

The 2-methoxy-pyridine-5-boronic acid (1.9 g, 12 mmol), the5-bromo-pyrimidine (1.2 eq) and K2CO3 (3 eq) were dissolved in a 10:1mixture of DME/H₂O (4 ml/mmol). The solution was degassed by bubbling N₂for 15 min and then Pd(PPh₃)₄ (0.05 eq) was added. The reaction mixturewas heated at 90° C. for 8 h an then cooled at room temperature, dilutedwith EA and filtered on a celite plug. The filtrate was washed withbrine. The separated organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. The obtained residue was purifiedby column chromatography. (SiO₂; Hexane/EA 30/1 to EA) 1.29 g (56%yield) of intermediate were obtained as white solid. A solution of5-(6-Methoxy-pyridin-3-yl)-pyrimidine (1.29 g, 6.9 mmol) in EtOH (4 ml)and HBr 48% (10 ml) was stirred at 90° C. for 7 h. The solvent wasevaporated and the crude A (as hydrobromide salt) was utilized in thenext step without any purification. Following general procedure H1A,compound 147 was prepared in 22% yield. 1H NMR (300 MHz, DMSO-d6) ppm9.12 (s, 2H), 9.11 (s, 1H), 8.32 (d, 1H), 8.06 (dd, 1H), 7.69 (m, 2H),7.56 (m, 2H), 6.68 (d, 1H)

Synthesis of Compound 148

For compound 148, A was prepared as stated for compound 147. Followinggeneral procedure H1A, compound 148 was prepared in 37% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.15 (br. s., 1H), 9.10 (s, 3H), 8.25 (d, 1H),8.04 (dd, 1H), 7.76 (s, 1H), 7.61 (d, 1H), 7.46 (dd, 1H), 7.15 (ddd,1H), 6.65 (d, 1H), 2.06 (s, 3H)

Synthesis of Compound 149

For compound 149, A was prepared as stated for compound 147. Followinggeneral procedure H1A, compound 149 was prepared in 16% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 9.12 (br. s., 3H), 8.26 (d, 1H), 8.04 (dd, 1H),7.32-7.66 (m, 5H), 6.66 (d, 1H)

Synthesis of Compound 150

For compound 150, A was prepared as stated for compound 130. Theprepared A was used in General procedure H1A to provide compound 150 in36.5% yield. ¹H NMR (300 MHz, DMSO-d₆) ppm 9.27 (s, 1H), 9.09 (s, 2H),8.33 (dd, 1H), 8.07 (dd, 1H), 7.86 (s, 4H), 7.36 (s, 2H), 6.70 (dd, 1H)

Synthesis of Compound 151

Following general procedure I, A was prepared in the following manner.

Following standard procedure for Suzuki coupling, the intermediateproduct was obtained by reaction of 2.5 g (13.3 mmol) of5-bromo-2-methoxy-pyridine. After purification (SiO₂; Hexane/EA 30/1 toEA) 2.1 g (87% yield) of the intermediate product were obtained as whitesolid. A solution of 6-Methoxy-[3,4′]bipyridinyl (2.1 g, 11.3 mmol) inEtOH (6 ml) and HBr 48% (12 ml) was stirred at 90° C. for 6 h. Thesolvent was evaporated and crude A (as hydrobromide salt) was utilizedin the next step without any purification. Following general procedureH1A, compound 151 was prepared in 12% yield. ¹H NMR (300 MHz, DMSO-d6)ppm 10.15 (s, 1H), 8.57 (br. s., 2H), 8.25 (d, 1H), 8.06 (dd, 1H), 7.75(dd, 1H), 7.66-7.73 (m, 2H), 7.62 (ddd, 1H), 7.46 (dd, 1H), 7.15 (ddd,1H), 6.64 (d, 1H), 2.07 (s, 3H)

Synthesis of Compound 152

For compound 152, A was prepared as described for compound 151. A wasused in the Chan Lam reaction, following General Procedure H1A toprovide compound 152 in 29% yield. ¹H NMR (300 MHz, DMSO-d6) ppm8.45-8.64 (m, 2H), 8.18 (dd, 1H), 8.00 (dd, 1H), 7.61-7.76 (m, 2H),7.37-7.61 (m, 5H), 6.63 (dd, 1H)

Synthesis of Compound 153

For compound 153, A was prepared as described for compound 151. A wasused in the Chan Lam reaction, following General Procedure H1A toprovide compound 153 in 36% yield. ¹H NMR (300 MHz, DMSO-d6) ppm8.45-8.70 (m, 2H), 8.32 (d, 1H), 8.07 (dd, 1H), 7.63-7.77 (m, 4H), 7.55(d, 2H), 6.66 (d, 1H)

Synthesis of Compound 154

Compound 154 was synthesized in the following manner. To a solution of2-pyridone (200 mg, 2.1 mmol) and 4-bromophenyl sulfonamide (994 mg, 4.2mmol) in 0.9 mL NMP, K₂CO₃ (292 mg, 2.1 mmol) and copper (I) iodide (120mg, 30%) were added, and the mixture heated at 160° C. for 30 secondsunder MW irradiation. The crude mixture was then dissolved in EA and theproduct precipitated out as a solid. The solid was purified by prep-HPLCto give 31.4 mg of compound 154 as a white solid (3% yield). ¹H NMR (300MHz, DMSO-d₆) ppm 7.93 (m, 2H), 7.69 (ddd, 1H), 7.63 (m, 2H), 7.53 (ddd,1H), 7.47 (s, 2H), 6.50 (dt, 1H), 6.35 (td, 1H)

Synthesis of Compound 155

For compound 155, A was prepared as described for compound 139. A wasused in the Chan Lam reaction, following General Procedure H1A toprovide compound 155 in 14% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 10.13(s, 1H), 8.03 (s, 1H), 7.86 (dd, 1H), 7.78 (d, 1H), 7.78 (dd, 1H), 7.70(t, 1H), 7.52-7.65 (m, 1H), 7.44 (t, 1H), 7.09 (ddd, 1H), 6.54 (dd, 1H),3.82 (s, 3H), 2.06 (s, 3H)

Synthesis of Compound 156

For compound 156, A was prepared as described for compound 139. A wasused in the Chan Lam reaction, following General Procedure H1A toprovide compound 156 in 20% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.04(s, 1H), 7.90-8.00 (m, 3H), 7.79 (d, 1H), 7.81 (dd, 1H), 7.68 (m, 2H),7.49 (br. s., 2H), 6.57 (dd, 1H), 3.83 (s, 3H)

Synthesis of Compound 157

For compound 157, A was prepared in the following manner.

The 2-methoxy-pyridine-5-boronic acid (1.9 g, 12 mmol), the5-bromo-pyrimidine (1.2 eq) and K₂CO₃ (3 eq) were dissolved in a 10:1mixture of DME/H₂O (4 mL/mmol). The solution was degassed by bubblingnitrogen for 15 min and then Pd(PPh₃)₄ (0.05 eq) was added. The reactionmixture was heated at 90° C. for 8 h and then cooled at roomtemperature, diluted with EtOAc and filtered on a celite plug. Thefiltrate was washed with brine. The separated organic phase was driedover Na₂SO₄ and concentrated under reduced pressure. The obtainedresidue was purified by column chromatography. (SiO₂; Hexanes/EtOAc 30/1to EtOAc) 1.29 g (56% yield) of pure product were obtained as whitesolid. A solution of 5-(6-Methoxy-pyridin-3-yl)-pyrimidine (1.29 g, 6.9mmol) in EtOH (4 ml) and HBr 48% (10 ml) was stirred at 90° C. for 7 h.The solvent was evaporated and the crude compound (as hydrobromide salt)was utilized in the next step without any purification. A was used inthe Chan Lam reaction, following General Procedure H1A to providecompound 157 in 11% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 9.10-9.17 (m,3H), 8.73-8.81 (m, 2H), 8.31 (dd, 1H), 8.07 (dd, 1H), 7.63-7.70 (m, 2H),6.70 (dd, 1H)

Synthesis of Compound 158

For compound 158, A was prepared as stated for compound 147. Followinggeneral procedure H1A, compound 158 was prepared in 37% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 9.02-9.21 (m, 3H), 8.32 (d, 1H), 8.07 (dd, 1H),7.97 (m, 2H), 7.75 (m, 2H), 7.51 (s, 2H), 6.69 (d, 1H)

Synthesis of Compound 159

Following general procedure I, A was prepared as follows.

Following standard procedure for Suzuki coupling, the intermediate wasobtained by reaction of 2.82 g (15 mmol) of 5-bromo-2-methoxy-pyridine.After purification (SiO₂; Hexane/EA 8/2) 1.8 g (59% yield) of pureintermediate were obtained as white solid. To a magnetically stirredsolution of 2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-pyridine (1 g, 4.9mmol), in 3 mL of EtOH, 10 mL of HBr were added. The mixture was heatedat 90° C. for 4 h. The reaction was cooled at room temperature. Thesolvent was evaporated under vacuum, afforded 1.34 g of A (quantitativeyield). Following general procedure H1A, compound 159 was prepared in11% yield. ¹H NMR (300 MHz, DMSO-d₆) ppm 10.13 (s, 1H), 7.74 (dd, 1H),7.69 (dd, 1H), 7.52-7.62 (m, 2H), 7.44 (dd, 1H), 7.11 (ddd, 1H), 6.58(dd, 1H), 2.39 (s, 3H), 2.22 (s, 3H), 2.06 (s, 3H)

Synthesis of Compound 160

For compound 160, A was prepared as stated for compound 159. Followinggeneral procedure H1A, compound 160 was prepared in 23% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 7.71 (dd, 1H), 7.42-7.61 (m, 6H), 6.58 (dd, 1H),2.39 (s, 3H), 2.22 (s, 3H)

Synthesis of Compound 161

Compound A for compound 161 was prepared as stated for compound 138. Theprepared compound A was used in General procedure H1A to providecompound 161. ¹H NMR (300 MHz, DMSO-d6) ppm 7.58 (dd, 1H), 7.38-7.54 (m,5H), 6.90 (d, 1H), 6.47 (d, 1H), 3.61-3.77 (m, 4H), 2.79-2.97 (m, 4H)

Synthesis of Compound 162

Compound A for compound 162 was prepared as stated for compound 138. Theprepared compound A was used in General procedure H1A to providecompound 162 in 65% yield. ¹H NMR (300 MHz, DMSO-d₆) ppm 10.16 (s, 1H),8.22 (dd, 1H), 8.06 (dd, 1H), 7.84 (d, 1H), 7.75 (t, 1H), 7.70 (d, 1H),7.57-7.67 (m, 1H), 7.46 (t, 1H), 7.16 (ddd, 1H), 6.64 (dd, 1H), 2.07 (s,3H)

Synthesis of Compound 163

For compound 163, A was prepared as stated for compound 159. Followinggeneral procedure H1A, compound 163 was prepared in 33% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 7.77 (dd, 1H), 7.45-7.71 (m, 5H), 6.60 (dd, 1H),2.39 (s, 3H), 2.23 (s, 3H)

Synthesis of Compound 164

For compound 164, A was prepared as stated for compound 159. Followinggeneral procedure H1A, compound 164 was prepared in 25% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.71-8.78 (m, 2H), 7.78 (dd, 1H), 7.54-7.66 (m,3H), 6.62 (dd, 1H), 2.40 (s, 3H), 2.23 (s, 3H)

Synthesis of Compound 165

For compound 165, A was prepared as described for compound 139. A wasused in the Chan Lam reaction, following General Procedure H1A toprovide compound 165 in 4.6% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 9.25(s, 1H), 9.04 (s, 2H), 8.08 (dd, 1H), 8.04 (d, 1H), 7.85 (dd, 1H), 7.79(d, 1H), 6.62 (dd, 1H), 3.84 (s, 3H)

Synthesis of Compound 166

Following General procedure H1A, compound 166 was synthesized. ‘1H NMR(300 MHz, DMSO-d₆) ppm 8.65-8.79 (m, 2H), 8.03 (dd, 1H), 7.65 (dd, 1H),7.50-7.60 (m, 2H), 6.51 (dd, 1H)

Synthesis of Compound 167

Following General Procedure L1, compound 167 was prepared in 13% yield.¹H NMR (300 MHz, DMSO-d6) ppm 7.55-7.66 (m, 3H), 7.35-7.54 (m, 2H), 6.95(d, 1H), 6.48 (d, 1H), 3.50-3.81 (m, 4H), 2.80-2.96 (m, 4H)

Synthesis of Compound 168

For compound 168, A was prepared as described for compound 139. A wasused in the Chan Lam reaction, following General Procedure H1A toprovide compound 168 in 7.4% yield. ¹H NMR (300 MHz, CDCl₃) ppm 8.80 (m,2H), 7.60 (d, 1H), 7.55 (dd, 1H), 7.49 (s, 1H), 7.46 (m, 2H), 7.41 (dd,1H), 6.73 (dd, 1H), 3.95 (s, 3H)

Synthesis of Compound 169

Following general procedure I, A was prepared as follows.

Following standard procedure for Suzuki coupling, the intermediate wasobtained by reaction of 2 g (10.64 mmol) of 5-bromo-2-methoxy-pyridine.After purification (SiO₂; hexane/EA 20/1 to EA) 2.1 g (87% yield) ofpure intermediate were obtained as white solid. A solution of6-methoxy-3,3′-bipyridine (1.7 g, 11.3 mmol) in EtOH (6 ml) and HBr 48%(12 ml) was stirred at 80° C. for 20 h. The solvent was evaporated andcrude A (as hydrobromide salt) was utilized in the next step without anypurification (quantitative yield). Following general procedure H1A, withthe addition of triethylamine, compound 169 was prepared in 14% yield.¹H NMR (300 MHz, DMSO-d6) ppm 8.89 (br. s., 1H), 8.51 (d, 1H), 8.18 (dd,1H), 8.07 (ddd, 1H), 8.01 (dd, 1H), 7.64-7.74 (m, 2H), 7.49-7.60 (m,2H), 7.44 (dd, 1H), 6.65 (dd, 1H)

Synthesis of Compound 170

Compound 170 is prepared as outlined in General Procedures K and J.Initially, 8 is prepared according to procedure K, then 9 was preparedaccording to General Procedure J by reaction of 2.3 g ethyl6-oxo-6,7-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (11.1 mmol),with 2.5 g of 4-isopropoxyphenylboronic acid (13.9 mmol). Afterpurification (SiO₂; DCM:MeOH 99:1) 2.1 g (55% yield) of 9 were obtained.Next, 10 was obtained starting from 2.1 g (6.2 mmol) of 9. Afterfiltration 1.8 g (93.3% yield) of 10 were obtained. Then, from 10 amideformation with morpholine was performed to provide compound 170 in 46.2%yield. ¹H NMR (300 MHz, DMSO-d6) ppm 11.32 (s, 1H), 7.80 (d, 1H),7.42-7.58 (m, 4H), 6.86 (s, 1H), 6.20 (d, 1H), 3.39-3.73 (m, 4H),1.74-1.99 (m, 4H)

Synthesis of Compound 171

For compound 171, A was prepared as stated for compound 159. Followinggeneral procedure H1A, compound 171 was prepared in 5% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 9.25 (s, 1H), 9.03 (s, 2H), 7.90 (dd, J=2.6, 0.6Hz, 1H), 7.65 (dd, J=9.5, 2.5 Hz, 1H), 6.66 (dd, J=9.4, 0.6 Hz, 1H),2.41 (s, 3H), 2.24 (s, 3H)

Synthesis of Compound 172

For compound 172, A was prepared as stated for compound 169. Followinggeneral procedure H1A, compound 172 was prepared in 21% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.88 (br. s., 1H), 8.51 (br. s., 1H), 8.10 (dd,1H), 8.05 (dt, 1H), 7.95-8.02 (m, 1H), 7.39-7.58 (m, 6H), 6.63 (d, 1H)

Synthesis of Compound 173

Compound 173 was synthesized in the following manner.

6-methoxynicotinaldehyde (1.0 g, 7.2 mmol) was dissolved in HBr 48% (10mL) and EtOH (3 mL) and the solution was heated at reflux for 2 h. Afterevaporation of volatiles, 1.6 g of the desired pyridone intermediate wasobtained. The intermediate was used in the next step without furtherpurification. To a solution of 6-oxo-1,6-dihydropyridine-3-carbaldehyde(640 mg, 5.2 mmol) in DCM (6 mL) and DMF (2 mL), Cu(OAc)₂ (1.8 g, 10.4mmol), phenyl boronic acid (1.2 g, 10.4 mmol), pyridine (0.8 g, 10.4mmol) and finely grounded, activated 4 Å molecular sieves (1 g) wereadded. The mixture was stirred at room temperature for 24 h. Aconcentrated solution of NH₄OH was added. The solvents were evaporatedunder vacuum, and the resulting crude was purified by chromatographiccolumn (SiO₂; Pet. Ether/EtOAc 10/1 to 0/1). 300 mg (48% yield) of thesecond intermediate were obtained as a white solid. To a solution of thesecond intermediate (6-oxo-1-phenyl-1,6-dihydropyridine-3-carbaldehyde,300 mg, 2.5 mmol) in of MeOH (20 mL), glyoxal (0.89 g, 10.4 mmol) wasadded at 0° C. Gaseous NH₃ was bubbled into the mixture at 0° C. for 1h. The reaction was warmed at room temperature and stirred for 24 h. Thesolvent was evaporated under vacuum and the resulting crude was purifiedby flash chromatography (SiO₂, Pet. Ether/EtOAc 10/1 to 0/1) and byreverse-phase preparative HPLC. 80 mg (14% yield) of compound 173 wereobtained. ¹H NMR (300 MHz, DMSO-d6) ppm 14.16 (br. S., 1H), 8.49 (d,1H), 8.03 (dd, 1H), 7.66 (s, 2H, 7.44-7.63 (m, 5H), 6.75 (d, 1H)

Synthesis of Compound 174

For compound 174, the iodopyridone intermediate was prepared asdescribed for compound 189, below. The iodopyridone intermediate wasthen used in a Stille coupling.

5-iodo-1-(pyridin-4-yl)pyridin-2(1H)-one (0.120 g, 0.4 mmol) wasdissolved in dry and degassed toluene (10 mL), previously degassed.Pd(PPh₃)₄ (0.023 g, 0.02 mmol) was then added and the mixture wasstirred for 10 minutes. 2-(tributylstannyl)thiazole (0.15 g, 0.4 mmol)was added and the reaction was heated at 90° C. for 4 h under nitrogenatmosphere. A large excess of a KF/H₂O solution was added and themixture was stirred for 1 h. The aqueous phase was extracted with EtOAc.The solvent was removed under reduced pressure and the crude waspurified by flash chromatography (SiO₂; EtOAc/MeOH 95:5) and thenthrough titration in CH₃CN. 38.7 mg (38% yield) of compound 174 wereobtained as a white solid. ¹H NMR (300 MHz, DMSO-d6) ppm 8.65-8.86 (m,2H), 8.31 (dd, 1H), 8.10 (dd, 1H), 7.86 (d, 1H), 7.72 (d, 1H), 7.58-7.68(m, 2H), 6.60-6.74 (m, 1H)

Synthesis of Compound 175

For compound 175, 10 was prepared as described for compound 170, then 10was mixed with N-methylpiperidine under the amide formation conditionsof General Procedure J to provide compound 175 in 28% yield. ¹H NMR (300MHz, DMSO-d6) ppm 11.18 (s, 1H), 7.74 (d, 1H), 7.22 (m, 2H), 7.05 (m,2H), 6.64 (s, 1H), 6.17 (d, 1H), 4.69 (spt, 1H), 3.42-3.80 (m, 4H),2.25-2.36 (m, 4H), 2.19 (s, 3H), 1.34 (d, 6H)

Synthesis of Compound 176

For compound 176, A was prepared as stated for compound 169. Followinggeneral procedure H1A, compound 176 was prepared in 7.6% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.89 (dd, 1H), 8.76 (dd, 2H), 8.52 (dd, 1H), 8.16(dd, 1H), 8.07 (ddd, 1H), 8.01 (dd, 1H), 7.62-7.69 (m, 2H), 7.44 (ddd,1H), 6.67 (dd, 1H)

Synthesis of Compound 177

For compound 177, 10 was prepared as described for compound 170, then 10was mixed with 3-methoxybenzylamine under the amide formation conditionsof General Procedure J to provide compound 177 in 46.5% yield. ¹H NMR(300 MHz, DMSO-d6) ppm

Synthesis of Compound 178

For compound 178, 10 was prepared as described for compound 170, then 10was mixed with benzylamine under the amide formation conditions ofGeneral Procedure J to provide compound 178 in 33.8% yield. ¹H NMR (300MHz, DMSO-d6) ppm 10.94 (s, 1H), 8.65 (t, 1H), 7.78 (d, 1H), 7.15-7.39(m, 7H), 6.96-7.12 (m, 3H), 6.18 (d, 1H), 4.68 (quin, 1H), 4.42 (d, 2H),1.33 (d, 6H)

Synthesis of Compound 179

For compound 179, 10 was prepared as described for compound 170, then 10was mixed with 2-aminothiazole under the amide formation conditions ofGeneral Procedure J to provide compound 179 in 37% yield. ¹H NMR (300MHz, DMSO-d6) ppm 12.23 (br. s., 1H), 11.38 (br. s., 1H), 7.83 (d, 1H),7.49 (d, 1H), 7.40 (s, 1H), 7.29 (m, 2H), 7.19 (d, 1H), 7.10 (m, 2H),6.25 (d, 1H), 4.71 (spt, 1H), 1.36 (d, 6H)

Synthesis of Compound 180

For compound 180, 10 was prepared as described for compound 170, then 10was mixed with N-methylpiperidine under the amide formation conditionsof General Procedure J to provide compound 180 in 33.8% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.48 (s, 1H), 7.78 (d, 1H), 7.46-7.58 (m, 4H),6.67 (s, 1H), 6.20 (d, 1H), 3.57-3.72 (m, 4H), 2.23-2.35 (m, 4H), 2.18(s, 3H)

Synthesis of Compound 181

For compound 181, 10 was prepared as described for compound 170, then 10was mixed with pyrole under the amide formation conditions of GeneralProcedure J to provide compound 181 in 46.2% yield. ¹H NMR (300 MHz,DMSO-d6) ppm 11.32 (s, 1H), 7.80 (d, 1H), 7.42-7.58 (m, 4H), 6.86 (s,1H), 6.20 (d, 1H), 3.39-3.73 (m, 4H), 1.74-1.99 (m, 4H)

Synthesis of Compound 182

For compound 182, 10 was prepared as described for compound 170, then 10was mixed with morphiline under the amide formation conditions ofGeneral Procedure J to provide compound 182 in 47% yield. ¹H NMR (300MHz, DMSO-d6) ppm 11.50 (br. s., 1H), 7.78 (d, 1H), 7.44-7.59 (m, 4H),6.71 (s, 1H), 6.20 (d, 1H), 3.48-3.75 (m, 8H)

Synthesis of Compound 183

For compound 183, the general procedure outlined for compound 189 wasused.

The iodopyridone intermediate above was obtained by reaction of 600 mg(2.7 mmol) of 5-iodo-2-pyridone with phenyl-boronic acid. Afterpurification (SiO₂; Hexane/Acetate/MeOH 1/1/0 to 0/10/1). 600 mg (75%yield) of pure intermediate were obtained as a pale yellow solid. TheSuzuki coupling, as outlined for compound 189, below, provided compound183 in 38% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.98 (s, 2H), 7.91 (dd,1H), 7.83 (dd, 1H), 7.36-7.62 (m, 5H), 6.54 (dd, 1H)

Synthesis of Compound 184

For compound 184, intermediate sulfonamide was prepared as follows.

A mixture of 2-methoxy-5-aminopyridine (10 g, 0.08 mol) in AcOH (125mL), and concentrated HCl (150 mL) was cooled at 0° C. in an ice/waterbath. A solution of NaNO₂ (4.0 g, 0.058 mol) in water (15 mL) was addeddropwise at 0° C. The resulting mixture was stirred for 45 minutes at 0°C. In a separate round bottom flask, 150 mL of concentrated HCl wasadded dropwise to a sodium bisulphite solution. The gaseous SO₂ thusformed was purged for 2-3 h into a third round bottom flask containingAcOH cooled at −20° C. CuCl₂ (18 g) was added, and the reaction wasstirred for 20 minutes at −20° C. The mixture was added dropwise to the2-methoxy-5-aminopyridine/AcOH/concentrated HCl mixture maintained at 0°C. The reaction was allowed to warm up to room temperature and stirredovernight. The mixture was quenched with water and the solid thus formedwas filtered, re-dissolved in DCM and filtered through celite. The clearsolution was dried over Na₂SO₄ and concentrated under vacuum to afford10.2 g (61% yield) of pure 6-methoxy-pyridine-3-sulfonyl chloride.6-Methoxy-pyridine-3-sulfonyl chloride (5.0 g, 0.025 mol) was dissolvedin DCM and cooled at 0° C. Gaseous NH₃ was bubbled in the solution for10 min. The resulting pale brown suspension was filtered and the solidwas triturated with water. The resulting white solid was filtered anddried under vacuum to afford 3.2 g (70.6% yield) of pure6-Methoxy-pyridine-3-sulfonamide. 6-Methoxy-pyridine-3-sulfonamide(0.752 g, 4.0 mmol) was dissolved in EtOH (6 mL). An excess of 48% HBraqueous solution (12 mL) was added and the reaction was heated at 90° C.for 20 h. The solvent was removed under reduced pressure and theresidual hydrobromic acid was further dried under reduced pressure, at40° C., to provide the intermediate sulfonamide in quantitative yield.The sulfonamide was used in General Procedure H1A to provide compound184 in 10% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.05 (dd, 1H), 7.79 (dd,1H), 7.62 (m, 2H), 7.55 (m, 2H), 7.36 (s, 2H), 6.67 (dd, 1H)

Synthesis of Compound 185

For compound 185, A was prepared in the following manner.

Following the general procedure I, 5-(2-fluorophenyl)-2-methoxypyridinewas obtained by reaction of 3 g (16 mmol) of 5-bromo-2-methoxy-pyridine.After purification (SiO₂; Pet. Ether/EtOAc 1/1 to 0/1), 750 mg (31%yield) of pure product was obtained as a white solid.5-(2-fluorophenyl)-2-methoxypyridine (750 mg) was dissolved in HBr 48%(10 mL) and EtOH (3 mL) and the solution was heated at reflux for 3 h.After evaporation of volatiles, 700 mg (quantitative yield) of thedesired pyridone were obtained as a white solid. Following generalprocedure H1A, compound 185 was prepared in 58% yield. ¹H NMR (300 MHz,DMSO-d6) ppm 10.13 (s, 1H), 7.69-7.90 (m, 3H), 7.51-7.65 (m, 2H),7.20-7.50 (m, 4H), 7.14 (dd, 1H), 6.60 (d, 1H), 2.06 (s, 3H)

Synthesis of Compound 186

For compound 186, A was prepared as described for compound 185.Following general procedure H1A, compound 186 was prepared in 43% yield.¹H NMR (300 MHz, DMSO-d6) ppm 7.82-7.88 (m, 1H), 7.78 (ddd, 1H),7.35-7.62 (m, 7H), 7.22-7.36 (m, 2H), 6.61 (dd, 1H)

Synthesis of Compound 187

For compound 187, A was prepared as described for compound 185.Following general procedure H1A, compound 187 was prepared in 58% yield.¹H NMR (300 MHz, DMSO-d6) ppm 7.90 (d, 1H), 7.79 (ddd, 1H), 7.67 (m,2H), 7.47-7.63 (m, 3H), 7.19-7.46 (m, 3H), 6.62 (dd, 1H)

Synthesis of Compound 188

The synthesis of compound 188 was achieved in the following manner.

5-(1H-imidazol-2-yl)pyridin-2(1H)-one (0.097 g, 0.6 mmol) was dissolvedin DCM (3 mL) and N,N-dimethylformammide (3 mL). Phenylboronic acid(0.087 g, 0.72 mmol), copper(II) acetate (0.21 g, 1.2 mmol), pyridine(0.095 g, 1.2 mmol) and 4 Å molecular sieves were added and the reactionwas stirred at room temperature in an open vessel for nine days. Thereaction was monitored by UPLC-MS. At the end of the reaction, aconcentrated solution of NH₄OH was added. Solvents were removed atreduced pressure, and the crude was purified by flash chromatography(SiO₂; EtOAc/MeOH 1:0 to 95:5). Two main products were recovered: 24 mgof compound 173 (10% yield) and 7 mg of compound 188 (2% yield). ¹H NMR(300 MHz, DMSO-d6) ppm 7.81-7.94 (m, 1H), 7.75 (d, 1H), 7.71 (br. s.,1H), 7.40-7.66 (m, 8H), 7.33 (dd, 1H), 7.22-7.30 (m, 2H), 6.50 (d, 1H)

Synthesis of Compound 189

For compound 189, an iodo-pyridone is the intermediate of the Suzukireaction.

To a solution of 5-iodo-pyridin-2-one (1 eq) in DCM (5 mL/mmol of arylhalide) and DMF (0.7 mL/mmol of aryl halide), Cu(OAc)₂ (2 eq), theappropriate boronic acid (1.2 eq), pyridine (2 eq) and finely grounded,activated 4 Å molecular sieves were added. The mixture was stirred atroom temperature in an open vessel for a variable time (from 12 hours to7 days). Fresh Boronic acid was further added in sluggish reactions. Aconcentrated solution of NH₄OH was added. The solvents were evaporatedunder vacuum and the resulting crude was absorbed on silica pad andpurified by flash chromatographic column (SiO₂; Pet. Ether/EtOAcmixture).

800 mg (4.2 mmol) of 5-iodo-2-pyridone with 4-pyridine-boronic acid.After purification (SiO₂; Pet. Ether/EtOAc/MeOH 1/1/0 to 0/10/1). 387 mg(31% yield) of pure product were obtained as a pale yellow solid.MS-ESI⁺: m/z=299 [MH⁺]

For the Suzuki coupling, the iodopyridone (1 eq), the appropriateboronic acid (1.2 eq) and K₂CO₃ (3 eq) were dissolved in a 10:1 mixtureof DME/H₂O (4 mL/mmol). The solution was degassed by bubbling N₂ for 15min and then Pd(PPh₃)₄ (0.05 eq) was added. The reaction mixture washeated at 90° C. for 18 h, after which time, BOC protecting group wascompletely cleaved. Mixture was cooled at room temperature, diluted withEtOAc and filtered on a celite plug. The filtrate was washed with brine.The separated organic phase was dried over Na₂SO₄ and concentrated underreduced pressure. The obtained residue was purified by columnchromatography (SiO₂; Pet. Ether/EtOAc mixture).

Compound 189 was obtained in 42% yield. ¹H NMR (300 MHz, DMSO-d6) ppm8.71-8.92 (m, 2H), 8.00 (s, 2H), 7.98 (dd, 1H), 7.88 (dd, 1H), 7.66-7.78(m, 2H), 6.60 (dd, 1H), 5.74 (br. s., 1H)

Synthesis of Compound 190

For compound 190, the intermediate sulfonamide was prepared as describedfor compound 184. The intermediate sulfonamide was used in GeneralProcedure H1A to provide compound 190 in 9% yield. ¹H NMR (300 MHz,DMSO-d6) ppm 7.99 (d, 1H), 7.78 (dd, 1H), 7.41-7.64 (m, 5H), 7.36 (s,2H), 6.66 (d, 1H)

Synthesis of Compound 191

For compound 191, A was prepared as stated for compound 147. Followinggeneral procedure H1A, compound 191 was prepared. ¹H NMR (300 MHz,DMSO-d6) ppm 9.13 (s, 1H), 9.12 (s, 1H), 8.76 (d, 1H), 8.67 (dd, 1H),8.35 (dd, 1H), 8.08 (dd, 1H), 8.02 (ddd, 1H), 7.61 (ddd, 1H), 6.70 (dd,1H)

Synthesis of Compound 192

For compound 192, A was prepared as stated for compound 169. Followinggeneral procedure H1A, compound 192 was prepared in 15% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.89 (d, 1H), 8.52 (dd, 1H), 8.17 (d, 1H), 8.06(ddd, 1H), 8.01 (dd, 1H), 7.96 (m, 2H), 7.74 (m, 2H), 7.49 (s, 2H), 7.43(ddd, 1H), 6.66 (d, 1H)

Synthesis of Compound 193

For compound 193, the iodopyridone intermediate was prepared asdescribed for compound 189 and 183, above. The iodopyridone was thenused in a Stille coupling.

5-iodo-1-phenylpyridin-2(1H)-one (0.088 g, 0.3 mmol) was dissolved indry and degassed toluene (7.5 mL/mmol). The catalyst was then added(0.017 g, 0.015 mmol) and the mixture was stirred for 10 minutes.2-(tributylstannyl)oxazole (0.107 g, 0.3 mmol) was added and thereaction was heated at 90° C. for 18 h under nitrogen atmosphere. Conc.NH₄OH was added. The solvent was removed at reduced pressure and thecrude was purified by flash chromatography (SiO₂; Pet. Ether/EtOAc 1:1)and then through titration in di-isopropylether. The residual productpresent in the mother liquor was recovered after purification withpreparative. 36 mg (30% yield) of compound 193 were obtained as a paleyellow solid. ¹H NMR (300 MHz, DMSO-d6) ppm 8.19 (dd, 1H), 8.14 (d, 1H),8.02 (dd, 1H), 7.43-7.61 (m, 5H), 7.32 (d, 1H), 6.66 (dd, 1H)

Synthesis of Compound 194

For compound 194, 10 was prepared as described for compound 170, then 10was mixed with pyrole under the amide formation conditions of GeneralProcedure J to provide compound 194 in 29% yield. ¹H NMR (300 MHz,DMSO-d6) ppm 10.72 (br. s., 1H), 7.76 (d, 1H), 7.22 (m, 2H), 7.05 (m,2H), 6.85 (s, 1H), 6.19 (d, 1H), 4.69 (quin, 1H), 3.39-3.72 (m, 4H),1.78-1.95 (m, 4H), 1.34 (d, 6H)

Synthesis of Compound 195

For compound 195, 10 was prepared as described for compound 170, then 10was mixed with 3-methoxyaniline under the amide formation conditions ofGeneral Procedure J to provide compound 195 in 75% yield. ¹H NMR (300MHz, DMSO-d6) ppm 11.26 (br. s., 1H), 9.86 (s, 1H), 7.83 (d, 1H),7.37-7.41 (m, 1H), 7.14-7.32 (m, 5H), 7.08 (m, 2H), 6.63 (ddd, 1H), 6.22(d, 1H), 4.70 (quin, 1H), 3.73 (s, 3H), 1.35 (d, 6H)

Synthesis of Compound 196

For compound 196, 10 was prepared as described for compound 170, then 10was mixed with 3-phenoxyaniline under the amide formation conditions ofGeneral Procedure J to provide compound 196 in 20% yield. ¹H NMR (300MHz, DMSO-d6) ppm 11.64 (s, 1H), 9.94 (s, 1H), 7.86 (d, 1H), 7.28-7.57(m, 10H), 7.15 (dddd, 1H), 7.04 (m, 2H), 6.72 (ddd, 1H), 6.24 (d, 1H)

Synthesis of Compound 197

For compound 197, 10 was prepared as described for compound 170, then 10was mixed with 3-aminobenzenesulfonamide under the amide formationconditions of General Procedure J to provide compound 197 in 21.4%yield. ¹H NMR (300 MHz, DMSO-d6) ppm 11.31 (s, 1H), 10.16 (s, 1H),8.12-8.18 (m, 1H), 7.89-8.01 (m, 1H), 7.84 (d, 1H), 7.43-7.57 (m, 2H),7.30-7.35 (m, 3H), 7.27 (m, 2H), 7.09 (m, 2H), 6.23 (d, 1H), 4.71 (quin,1H), 1.35 (d, 6H)

Synthesis of Compound 198

For compound 198, 10 was prepared as described for compound 170, then 10was mixed with 3-methylaminopyridine under the amide formationconditions of General Procedure J to provide compound 198 in 28.4%yield. ¹H NMR (300 MHz, DMSO-d6) ppm 11.02 (s, 1H), 8.62-8.92 (m, 1H),8.35-8.58 (m, 2H), 7.79 (d, 1H), 7.17-7.34 (m, 4H), 6.98-7.14 (m, 3H),6.19 (d, 1H), 4.68 (quin, 1H), 4.43 (d, 2H), 1.33 (d, 6H)

Synthesis of Compound 199

For compound 199, 10 was prepared as described for compound 170, then 10was mixed with 3-phenoxyaniline under the amide formation conditions ofGeneral Procedure J to provide compound 199 in 47% yield. ¹H NMR (300MHz, DMSO-d6) ppm 11.28 (s, 1H), 9.92 (s, 1H), 7.81 (d, 1H), 7.35-7.49(m, 4H), 7.31 (dd, 1H), 7.20-7.27 (m, 3H), 7.10-7.19 (m, 1H), 6.98-7.10(m, 4H), 6.72 (ddd, 1H), 6.21 (d, 1H), 4.69 (quin, 1H), 1.34 (d, 6H)

Synthesis of Compound 200

Following General Procedure L2, compound 200 was prepared in 10% yield.¹H NMR (300 MHz, DMSO-d6) ppm 7.45-7.55 (m, 2H), 7.34-7.45 (m, 4H), 6.57(d, 1H), 6.45 (dd, 1H), 2.99-3.12 (m, 4H), 1.78-1.97 (m, 4H)

Synthesis of Compound 201

For compound 201, A was prepared as described for compound 185.Following general procedure H1A, compound 201 was prepared in 13% yield.¹H NMR (300 MHz, DMSO-d6) ppm 9.25 (s, 1H), 9.07 (s, 2H), 8.06 (d, 1H),7.79-7.88 (m, 1H), 7.55-7.65 (m, 1H), 7.20-7.47 (m, 3H), 6.66 (dd, 1H)

Synthesis of Compound 202

Compound A for compound 202 was prepared as stated for compound 116. Theprepared compound A was used in General procedure H1A to providecompound 202 in 8% yield. ¹H NMR (300 MHz, DMSO-d₆) 9.27 (s, 1H), 8.91(s, 2H), 7.29-7.35 (m, 1H), 7.11 (dt, 1H), 6.71 (d, 1H), 1.63-1.83 (m,1H), 0.86-1.02 (m, 2H), 0.51-0.69 (m, 2H)

Synthesis of Compound 203

For compound 203, the iodopyridone intermediate was obtained asdescribed for compound 189.

The product was obtained by reaction of 500 mg (2.25 mmol) of5-iodo-2-pyridone with 4-trifluoromethoxy-phenyl-boronic acid. Afterflash chromatography (SiO₂; Pet. Ether/EtOAc 2:1) 300 mg (35% yield) ofthe intermediate were obtained as a white solid. MS-ESI⁺: m/z=380.9[MH⁺] The iodopyridone was then used in a Stille coupling.

5-iodo-1-(4-(trifluoromethoxy)phenyl)pyridin-2(1H)-one (0.19 g, 0.5mmol) was dissolved in dry and degassed toluene (10 mL). Pd(PPh₃)₄(0.029 g, 0.025 mmol) was then added and the mixture was stirred for 10minutes. 2-(tributylstannyl)thiazole (0.187 g, 0.5 mmol) was added andthe reaction was heated at 90° C. for 4 h under nitrogen atmosphere. Alarge excess of a KF/H₂O solution was added and the mixture was stirredfor 1 h. The aqueous phase was extracted with EtOAc. The solvent wasremoved under reduced pressure and the crude was purified by flashchromatography (SiO₂; Pet. Ether/EtOAc 7:3 to Hex/EtOAc 1:1) and thenthrough titration in a Pet. Ether/EtOAc mixture. 62.5 mg (37% yield) ofcompound 203 were obtained as a white solid. ¹H NMR (300 MHz, DMSO-d6)ppm 8.30 (dd, 1H), 8.09 (dd, 1H), 7.85 (d, 1H), 7.60-7.75 (m, 3H), 7.55(m, 2H), 6.66 (dd, 1H)

Synthesis of Compound 204

For compound 204, 10 was prepared as described for compound 170, then 10was mixed with 3-chloroaniline under the amide formation conditions ofGeneral Procedure J to provide compound 204 in 32.3% yield. ¹H NMR (300MHz, DMSO-d6) ppm 11.69 (s, 1H), 10.04 (s, 1H), 7.82-7.97 (m, 2H), 7.63(ddd, 1H), 7.46-7.59 (m, 4H), 7.27-7.41 (m, 2H), 7.10 (ddd, 1H), 6.26(d, 1H)

Synthesis of Compound 205

For compound 205, 10 was prepared as described for compound 170, then 10was mixed with 2-methylaminotetrahydrofuran under the amide formationconditions of General Procedure J to provide compound 205 in 16.5%yield. ¹H NMR (300 MHz, DMSO-d6) ppm 11.15-11.41 (m, 1H), 8.11-8.29 (m,1H), 7.81 (d, 1H), 7.47-7.63 (m, 4H), 7.04 (d, 1H), 6.20 (d, 1H),3.83-3.97 (m, 1H), 3.68-3.81 (m, 1H), 3.53-3.67 (m, 1H), 3.18-3.37 (m,2H), 1.69-1.98 (m, 3H), 1.43-1.60 (m, 1H)

Synthesis of Compound 206

For compound 206, 10 was prepared as described for compound 170, then 10was mixed with 4-phenoxyaniline under the amide formation conditions ofGeneral Procedure J to provide compound 206 in 34.7% yield. ¹H NMR (300MHz, DMSO-d6) ppm 11.25 (s, 1H), 9.91 (s, 1H), 7.83 (d, 1H), 7.60-7.75(m, 2H), 7.31-7.44 (m, 2H), 7.19-7.31 (m, 3H), 7.04-7.16 (m, 3H),6.90-7.04 (m, 4H), 6.22 (d, 1H), 4.64-4.76 (m, 1H), 1.35 (d, 6H)

Synthesis of Compound 207

For compound 207, general procedures K and J were used to obtaincompound 207 in 70% yield. ¹H NMR (300 MHz, CDCl₃): ppm 1.34 (t, J=7.1Hz, 3H); 4.30 (q, J=7.1 Hz, 2H); 6.47 (d, J=9.3 Hz, 1H); 7.03 (d, J=2.4Hz, 1H); 7.26-7.43 (m, 2H); 7.57-7.69 (m, 4H); 8.27 (s, 1H); MS-ESI:m/z=283.1 [M+1]+

Synthesis of Compound 208

For compound 208, general procedures K and J were used to obtaincompound 208 in 41% yield. ¹H NMR (300 MHz, CDCl₃): ppm 1.34 (t, J=7.2Hz, 3H); 4.30 (q, J=7.1 Hz, 2H); 6.54 (d, J=9.3 Hz, 1H); 6.79 (d, J=8.7Hz, 2H); 7.01-7.11 (m, 3H); 7.76 (d, J=9.0 Hz, 1H); 7.89-8.57 (br., 1H);8.425 (s, 1H); MS-ESI: m/z=299.0 [M+1]⁺

Synthesis of Compound 209

For compound 209, the following synthesis was used.

To a mixture of 209-1 (45.0 g, 381.4 mmol), para-toluenesulfonylchloride (80.1 g, 421.6 mmol) and a catalytic amount of tetrabutylammonium bromide (TBABr) in toluene (540 ml) was added aq. NaOH (288.0 gin 900 ml water, 7.2 mol). The biphasic solution was stirred at ambienttemperature for 4 h, and then extracted twice with toluene. The organicphase was dried over anhydrous Na₂SO₄ and concentrated. The crudeproduct was triturated in ethyl acetate/petroleum ether (V:V=1:20) andfiltrated to afford the compound 209-2 (90 g, 87% yield). MS-ESI:m/z=273.1 [M+1]⁺

A solution of 209-2 (50.0 g, 183.8 mmol) in dry THF cooled to −78° C.and n-BuLi (81 ml, 2.5 M in hexane) was added over 20 minutes. Theresulted solution was maintained at −78° C. for 1 h, and then a solutionof BrCl₂CCCl₂Br (71.0 g, 220.5 mmol) in dry THF was added. The mixturewas stirred −78° C. for 30 min and allowed to warm slowly to roomtemperature. The solvent was removed under vacuum and the residue waspartitioned between EtOAc and water. The organic layer was dried overanhydrous Na₂SO₄ and concentrated. The crude product was purified bycolumn chromatography (5% ethyl acetate in petroleum ether to 20% ethylacetate in petroleum ether as the eluent) to afford 209-3 (37 g, 58%yield). MS-ESI: m/z=351.0 [M+1]⁺

A mixture of 209-3 (30 g, 0.085 mol), methanol (850 mL) and aqueouspotassium hydroxide (5 mol/L, 100 mL) was heated under reflux overnight.The majority of the solvent was removed under vacuum, and the residuewas partitioned between EtOAc and water. The organic layer was driedover anhydrous Na₂SO₄ and concentrated to give 209-4 (24 g, 80% yield)which was used without further purification. ¹H NMR (400 MHz, DMSO):6.550 (s, 1H); 7.039 (dd, J=5.2 Hz, J=3.2 Hz, 1H); 7.857 (dd, J=1.6 Hz,J=3.2 Hz, 1H); 8.155 (q, J=1.6 Hz, 1H); 12.418 (br, 1H)

mCPBA (14.0 g, 81.4 mmol) was added into a solution of 209-4 (8.0 g,40.8 mmol) in THF (140 ml) at 0° C., and then the reaction was warmed upthe room temperature for 1 h and quenched with saturated Na₂S₂O₃. Thesolution was concentrated after filtering. The crude was purified bycolumn chromatography (0-10% methanol in ethyl acetate as the eluent) toafford 209-5 (6.3 g, 73% yield). ¹H NMR (400 MHz, DMSO): 6.698 (s, 1H);7.055 (t, J=6.4 Hz, 1H); 7.660 (d, J=6.0 Hz, 1H); 8.099 (d, J=6.0 Hz,1H)

A mixture of 209-5 (3.5 g, 16.5 mmol) and acetic acid anhydride washeated at its reflux temperature for 1.5 h. The solution was thenevaporated. The residue was mixed with methanol and Et₃N at roomtemperature for 2 h. The solution was concentrated and the residue waspartitioned between EtOAc and water. The organic layer was dried overanhydrous Na₂SO₄ and concentrated. The crude product was purified bycolumn chromatography (10% ethyl acetate/petroleum) to afford 209-6 (1.4g, 40% yield). ¹H NMR (300 MHz, DMSO): 6.337 (d, J=8.1 Hz, 1H); 6.359(s, 1H); 7.662 (d, J=8.1 Hz, 1H) MS-ESI: m/z=214.1 [M+1]⁺

A solution of 209-6 (150 mg, 0.71 mmol) and triethylamine (470 mg, 4.2mmol) in THF (5 mL) was stirred for 15 min before the addition of(Boc)₂O (0.907 g, 4.2 mmol). The solution was stirred at roomtemperature overnight. Most of the solvent was removed under vacuum toget a residue, then it was partitioned between water (50 mL) and DCM(100 mL), the organic layer was separated and the aqueous layer wasextracted with DCM (50 mL×2). The combined organic layer was washed withwater (100 mL) and brine (100 mL), dried over Na₂SO₄ and concentrated togive a residue, which was purified by Prep-TLC (25% ethyl acetate inpetroleum ether as the eluent) to give 209-7 (250 mg, yield 85%). ¹H NMR(400 MHz, CDCl₃): 1.558 (s, 9H); 1.684 (s, 9H); 6.673 (s, 1H); 6.970 (d,J=8.4 Hz, 1H); 7.824 (d, J=8.4 Hz, 1H); MS-ESI: m/z=436.9 [M+23]⁺

A mixture of 209-7 (550 mg, 1.33 mmol), K₂CO₃ (200 mg, 1.45 mmol) andmethanol (8 mL) was stirred at rt for 1 h. Methanol was removed beforethe addition of water (50 mL), then it was extracted with DCM (50 mL×3).Combined DCM was washed with water and brine, dried over Na₂SO₄ andconcentrated to give a residue, which was isolated by prep-TLC (50%ethyl acetate in petroleum ether as the eluent) to give 209-8 (130 mg,31.2%) as a white solid. ¹H NMR (400 MHz, CDCl₃): 1.699 (s, 9H); 6.404(d, J=9.2 Hz, 1H); 6.488 (s, 1H); 7.518 (d, J=9.2 Hz, 1H); MS-ESI:m/z=352.9 [M+39]⁺

A mixture of 209-8 (50 mg, 0.16 mmol), 4-isopropoxybenzyl boric acid(100 mg, 0.73 mmol), pyridine (0.26 mL, 3.2 mmol) and anhydrous Cu(OAC)₂(10 mg, 0.05 mmol) in DCM (2 mL) was stirred over night open to air. Themixture was filtrated and evaporated to give a residue, which wasisolated by Prep-TLC (20% ethyl acetate in petroleum ether as theeluent) to give 209-9 (50 mg, 78.6%) as a white solid. ¹H NMR (400 MHz,CDCl₃): 1.345 (d, J=8.0 Hz, 6H); 1.412 (s, 1H); 4.489 (m, J=8.0 Hz, 1H);6.596 (s, 1H); 6.785 (d, J=11.2 Hz, 1H); 6.852-6.906 (m, 2H);7.031-7.085 (m, 2H); 7.725 (d, J=11.2 Hz, 1H); MS-ESI: m/z=448.8 [M+1]⁺

A solution of 209-9 (50 mg, 0.112 mmol) in DCM/TFA (V:V=1:1) was stirredat room temperature for 3 h. All the solvents were removed byevaporation to give a residue. It was isolated by Prep-TLC (25% ethylacetate in petroleum ether as the eluent) to give compound 209 (30 mg,68.5%) as a white solid. ¹H NMR (400 MHz, CDCl₃): 1.350 (d, J=6.0 Hz,6H); 4.509 (m, J=6.0 Hz, 1H); 6.440 (d, J=2.0 Hz, 1H); 6.674 (d, J=8.4Hz, 1H); 6.899 (d, J=8.8 Hz, 2H); 7.053 (d, J=8.8 Hz, 2H); 7.774 (d,J=8.4 Hz, 1H); 8.683 (br, 1H); MS-ESI: m/z=349.2 [M+1]⁺

Synthesis of Compound 210

For compound 210, compound 247 was used as an intermediate in generalprocedure J amide formation to form compound 210 in 20.4% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.65 (br. s., 1H), 9.86 (s, 1H), 7.87 (d, 1H),7.45-7.63 (m, 4H), 7.38-7.44 (m, 1H), 7.14-7.34 (m, 3H), 6.63 (ddd, 1H),6.24 (d, 1H), 3.73 (s, 3H)

Synthesis of Compound 211

For compound 211, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 211 in 52% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.53 (br. s., 1H), 9.84 (br. s., 1H), 7.85 (d,1H), 7.34-7.49 (m, 5H), 7.29 (s, 1H), 7.16-7.27 (m, 2H), 6.56-6.71 (m,1H), 6.23 (d, 1H), 3.73 (s, 3H)

Synthesis of Compound 212

For compound 212, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 212 in 27.9% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.18 (br. s., 1H), 7.70-7.85 (m, 1H), 7.26-7.47(m, 4H), 6.85 (s, 1H), 6.08-6.28 (m, 1H), 3.39-3.72 (m, 4H), 1.76-1.94(m, 4H)

Synthesis of Compound 213

For compound 213, general procedures K and J were used to obtaincompound 213 in 61% yield. ¹H NMR (300 MHz, DMSO-d₆) ppm 12.49 (br. s.,1H), 7.92 (d, 2H), 7.82 (d, 1H), 7.61 (d, 2H), 7.01 (s, 1H), 6.24 (d,1H)

Synthesis of Compound 214

For compound 214, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 214 in 17.5% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.17 (br. s., 1H), 8.63 (br. s., 1H), 7.80 (d,1H), 7.19-7.46 (m, 9H), 7.04 (s, 1H), 6.18 (d, 1H), 4.42 (d, 2H)

Synthesis of Compound 215

For compound 215, general procedures K and J were used to obtaincompound 215 in 93.3% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 12.41 (s,1H), 7.76 (d, 1H), 7.20 (m, 2H), 7.04 (m, 2H), 6.97 (s, 1H), 6.20 (d,1H), 4.68 (quin, 1H), 1.34 (d, 6H)

Synthesis of Compound 216

For compound 216, general procedures K and J were used to obtaincompound 216 in 93.6% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.77 (d, 1H),7.24-7.50 (m, 4H), 6.89 (s, 1H), 6.19 (d, 1H)

Synthesis of Compound 217

For compound 217, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 217 in 31.6% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.60 (br. s., 1H), 10.11 (br. s., 1H), 8.18 (s,1H), 7.92 (br. s., 1H), 7.84 (d, 1H), 7.22-7.55 (m, 9H), 6.20 (d, 1H)

Synthesis of Compound 218

For compound 218, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 218 in 30.7% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.40 (br. s., 1H), 7.76 (d, 1H), 7.27-7.50 (m,4H), 6.66 (s, 1H), 6.18 (d, 1H), 3.51-3.75 (m, 4H), 2.23-2.37 (m, 4H),2.18 (s, 3H)

Synthesis of Compound 219

For compound 219, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 219 in 21.9% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.71 (s, 1H) 9.87 (s, 1H) 7.94 (d, 2H) 7.89 (d,1H) 7.65 (d, 2H) 7.37-7.45 (m, 1H) 7.33 (s, 1H) 7.14-7.29 (m, 2H)6.57-6.69 (m, 1H) 6.26 (d, 1H) 3.73 (s, 3H)

Synthesis of Compound 220

For compound 220, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 220 in 47.5% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.53 (br. s., 1H) 7.92 (m, 2H) 7.80 (d, 1H) 7.62(m, 2H) 6.72 (s, 1H) 6.21 (d, 1H) 3.49-3.72 (m, 8H)

Synthesis of Compound 221

For compound 221, compound 247 was used as an intermediate in generalprocedure J amide formation to form compound 221 in 37.9% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.63 (s, 1H), 9.93 (s, 1H), 7.88 (d, 1H),7.65-7.76 (m, 2H), 7.47-7.62 (m, 4H), 7.32-7.42 (m, 2H), 7.31 (d, 1H),7.05-7.16 (m, 1H), 6.91-7.05 (m, 4H), 6.25 (d, 1H)

Synthesis of Compound 222

For compound 222, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 222 in 30.9% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.51 (s, 1H) 9.91 (s, 1H) 7.86 (d, 1H) 7.65-7.76(m, 2H) 7.32-7.50 (m, 6H) 7.29 (s, 1H) 7.06-7.15 (m, 1H) 6.92-7.05 (m,4H) 6.24 (d, 1H)

Synthesis of Compound 223

For compound 223, general procedure K is modified as follows.

To a solution of 4 (5 g crude) in dry DMF (50 mL) anhydrous potassiumcarbonate (10.9 g, 79 mmol) and methyl iodide (2.5 mL, 0.039 mol) wereadded. The reaction was stirred at room temperature overnight. Themixture was filtered and the residue was washed with methanol. Motherliquors were concentrated and the obtained crude product was purified bycolumn chromatography (SiO₂, hexanes:EtOAc 7:3) to obtain 1.5 g of ayellow solid (9:1 mixture of1-Methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester and1-Methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester. Thisintermediate was then used in the subsequent reactions of generalprocedure K to obtain a methyl version of intermediate 8 for use ingeneral procedure J. Following this modified procedure, compound 223 wasobtained in 94% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 12.98 (br. s., 1H)8.18 (d, 1H) 7.44 (m, 2H) 7.36 (m, 2H) 7.20 (s, 1H) 6.88 (d, 1H) 3.82(s, 3H)

Synthesis of Compound 224

For compound 224, compound 247 was used as an intermediate in generalprocedure J amide formation to form compound 224 in 13.4% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 1.36 (br. s., 1H) 8.65 (t, 1H) 7.82 (d, 1H)7.46-7.59 (m, 4H) 7.21 (t, 1H) 7.07 (s, 1H) 6.73-6.88 (m, 3H) 6.21 (d,1H) 4.39 (d, 2H) 3.72 (s, 3H)

Synthesis of Compound 225

For compound 225, general procedures K and J were used to obtaincompound 225 in 83.7% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.78 (d, 1H),7.60 (m, 2H), 7.38 (m, 2H), 6.94 (s, 1H), 6.20 (d, 1H)

Synthesis of Compound 226

For compound 226, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 226 in 23.5% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.44 (s, 1H) 7.91 (m, 2H) 7.82 (d, 1H) 7.60 (m,2H) 6.87 (s, 1H) 6.21 (d, 1H) 3.39-3.73 (m, 4H) 1.77-1.98 (m, 4H)

Synthesis of Compound 227

For compound 227, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 227 in 37.2% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.41 (br. s., 1H) 7.76 (d, 1H) 7.29-7.47 (m, 4H)6.62-6.74 (m, 1H) 6.19 (d, 1H) 3.51-3.72 (m, 8H)

Synthesis of Compound 228

For compound 228, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 228 in 47.6% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.58 (br. s., 1H) 10.01 (br. s., 1H) 7.80-7.94(m, 2H) 7.56-7.66 (m, 1H) 7.23-7.50 (m, 6H) 7.02-7.15 (m, 1H) 6.23 (d,1H)

Synthesis of Compound 229

For compound 229, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 229 in 19% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.55 (br. s., 1H), 7.92 (m, 2H), 7.78 (d, 1H),7.62 (m, 2H), 6.68 (s, 1H), 6.19 (d, 1H), 3.52-3.75 (m, 4H), 2.23-2.35(m, 4H), 2.18 (s, 3H)

Synthesis of Compound 230

For compound 230, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 230 in 23% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.43 (br. s., 1H), 7.92 (m, 2H), 7.80 (d, 1H),7.62 (m, 2H), 6.70 (s, 1H), 6.13-6.27 (m, 1H), 4.51-4.72 (m, 1H), 2.92(s, 3H), 1.12 (d, 6H)

Synthesis of Compound 231

For compound 231, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 231 in 23% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.23 (br. s., 1H), 7.77 (d, 1H), 7.27-7.48 (m,4H), 6.69 (s, 1H), 6.18 (d, 1H), 4.45-4.73 (m, 1H), 2.92 (s, 3H), 1.13(d, 6H)

Synthesis of Compound 232

For compound 232, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 232 in 36% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.37 (br. s., 1H), 8.19 (br. s., 1H), 7.94 (m,2H), 7.82 (d, 1H), 7.63 (m, 2H), 7.04 (s, 1H), 6.20 (d, 1H), 3.83-3.98(m, 1H), 3.68-3.80 (m, 1H), 3.53-3.66 (m, 1H), 3.13-3.36 (m, 2H),1.67-1.99 (m, 3H)

Synthesis of Compound 233

For compound 233, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 233 in 19% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.34 (br. s., 1H), 7.77 (d, 1H), 7.61 (m, 2H),7.39 (m, 2H), 6.69 (s, 1H), 6.18 (d, 1H), 4.45-4.72 (m, 1H), 2.92 (s,3H), 1.13 (d, 6H)

Synthesis of Compound 234

For compound 234, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 234 in 35% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.80 (br. s., 1H), 10.01 (br. s., 1H), 7.81-8.01(m, 4H), 7.56-7.70 (m, 3H), 7.26-7.42 (m, 2H), 7.03-7.16 (m, 1H), 6.25(d, 1H)

Synthesis of Compound 235

For compound 235, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 235 in 19% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.34 (br. s., 1H), 7.77 (d, 1H), 7.61 (m, 2H),7.39 (m, 2H), 6.69 (s, 1H), 6.18 (d, 1H), 4.45-4.72 (m, 1H), 2.92 (s,3H), 1.13 (d, 6H)

Synthesis of Compound 236

For compound 236, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 236 in 45% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.39 (br. s., 1H), 8.44 (br. s., 1H), 7.91 (m,2H), 7.83 (d, 1H), 7.61 (m, 2H), 7.25-7.38 (m, 4H), 7.17-7.24 (m, 1H),7.14 (s, 1H), 6.21 (d, 1H), 4.99-5.21 (m, 1H), 1.44 (d, 3H)

Synthesis of Compound 237

For compound 237, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 237 in 25.1% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 7.76 (d, 1H), 7.60 (m, 2H), 7.39 (m, 2H), 6.69(s, 1H), 6.17 (d, 1H), 3.52-3.73 (m, 8H)

Synthesis of Compound 238

For compound 238, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 238 in 38% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.44 (br. s., 1H), 8.62 (br. s., 1H), 7.92 (m,2H), 7.82 (d, 1H), 7.63 (m, 2H), 7.15-7.36 (m, 5H), 6.92-7.14 (m, 1H),6.02-6.29 (m, 1H), 4.41 (d, 2H)

Synthesis of Compound 239

For compound 239, compound 215 was used as an intermediate in generalprocedure J amide formation to form compound 239 in 34% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.91 (s, 1H), 7.75 (d, 1H), 7.22 (m, 2H), 7.06(m, 2H), 6.67 (s, 1H), 6.17 (d, 1H), 4.64-4.75 (m, 1H), 4.53-4.64 (m,1H), 2.91 (s, 3H), 1.33 (d, 6H), 1.12 (d, 6H)

Synthesis of Compound 240

For compound 240, compound 215 was used as an intermediate in generalprocedure J amide formation to form compound 240 in 20% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.88 (s, 1H), 8.22 (t, 1H), 7.76 (d, 1H), 7.25(m, 2H), 7.08 (m, 2H), 6.99 (s, 1H), 6.18 (d, 1H), 4.58-4.80 (m, 1H),3.81-3.95 (m, 1H), 3.67-3.81 (m, 1H), 3.53-3.67 (m, 1H), 3.12-3.37 (m,2H), 1.67-1.96 (m, 3H), 1.41-1.60 (m, 1H), 1.34 (d, 6H)

Synthesis of Compound 241

For compound 241, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 241 in 25.3% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.23-8.33 (m, 1H), 7.84-8.00 (m, 3H), 7.72-7.80(m, 1H), 7.69 (d, 2H), 7.49-7.58 (m, 2H), 7.14 (br. s., 1H), 6.10 (br.s., 1H), 3.14 (s, 3H)

Synthesis of Compound 242

For compound 242, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 242 in 31.8% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 12.25 (br. s., 1H), 11.67 (br. s., 1H), 7.86 (d,1H), 7.66 (m, 2H), 7.39-7.56 (m, 4H), 7.20 (d, 1H), 6.26 (d, 1H)

Synthesis of Compound 243

For compound 243, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 243 in 31.8% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.50 (br. s., 1H), 7.75 (d, 1H), 7.59 (m, 2H),7.39 (m, 2H), 6.65 (s, 1H), 6.15 (d, 1H), 3.53-3.80 (m, 4H), 2.23-2.35(m, 4H), 2.18 (s, 3H)

Synthesis of Compound 244

For compound 244, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 244 in 19.7% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.32 (br. s., 1H), 7.79 (d, 1H), 7.60 (m, 2H),7.38 (m, 2H), 6.86 (s, 1H), 6.20 (d, 1H), 3.56 (br. s., 4H), 1.87 (br.s., 4H)

Synthesis of Compound 245

For compound 245, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 245 in 26.7% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.68 (br. s., 1H), 10.03 (s, 1H), 7.80-7.94 (m,2H), 7.58-7.69 (m, 3H), 7.39-7.47 (m, 2H), 7.27-7.39 (m, 2H), 7.10 (ddd,1H), 6.24 (d, 1H)

Synthesis of Compound 246

For compound 246, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 246 in 31.9% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.62 (s, 1H), 9.92 (s, 1H), 7.87 (d, 1H),7.66-7.75 (m, 2H), 7.58-7.66 (m, 2H), 7.32-7.48 (m, 4H), 7.29 (s, 1H),7.05-7.17 (m, 1H), 6.92-7.05 (m, 4H), 6.24 (d, 1H)

Synthesis of Compound 247

For compound 247, general procedures K and J were used to obtaincompound 247 in 81.5% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.80 (d, 1H),7.40-7.60 (m, 4H), 6.99 (s, 1H), 6.22 (d, 1H)

Synthesis of Compound 248

For compound 248, general procedures K and J were used to obtaincompound 248 in 90% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 12.32 (br. s.,1H), 9.69 (br. s., 1H), 7.76 (d, 1H), 7.33 (dd, 1H), 6.97 (s, 1H), 6.90(ddd, 1H), 6.72 (ddd, 1H), 6.67 (t, 1H), 6.20 (d, 1H)

Synthesis of Compound 249

For compound 249, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 249 in 15.2% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.62 (t, 1H), 7.81 (d, 1H), 7.62 (m, 2H), 7.41(m, 2H), 7.22 (t, 1H), 7.06 (s, 1H), 6.73-6.88 (m, 3H), 6.20 (d, 1H),4.39 (d, 2H), 3.72 (s, 3H)

Synthesis of Compound 250

For compound 250, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 250 in 34.2% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.12 (s, 1H), 8.76 (br. s., 1H), 8.32-8.58 (m,2H), 7.92 (m, 2H), 7.84 (d, 1H), 7.63 (m, 2H), 7.21-7.30 (m, 2H), 7.09(s, 1H), 6.21 (d, 1H), 4.33-4.53 (m, 2H)

Synthesis of Compound 251

For compound 251, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 251 in 31.1% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.12 (s, 1H), 8.76 (br. s., 1H), 8.32-8.58 (m,2H), 7.92 (m, 2H), 7.84 (d, 1H), 7.63 (m, 2H), 7.21-7.30 (m, 2H), 7.09(s, 1H), 6.21 (d, 1H), 4.33-4.53 (m, 2H)

Synthesis of Compound 252

For compound 252, compound 215 was used as an intermediate in generalprocedure J amide formation to form compound 252 in 27% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.73 (br. s., 1H), 8.44 (d, 1H), 7.77 (d, 1H),7.13-7.40 (m, 7H), 7.00-7.13 (m, 3H), 6.18 (d, 1H), 4.99-5.20 (m, 1H),4.58-4.76 (m, 1H), 1.44 (d, 3H), 1.33 (d, 6H)

Synthesis of Compound 253

For compound 253, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 253 in 23.3% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.62 (s, 1H), 9.93 (s, 1H), 7.77-7.93 (m, 1H),7.57-7.67 (m, 2H), 7.35-7.49 (m, 6H), 7.26-7.35 (m, 2H), 7.09-7.21 (m,1H), 6.97-7.09 (m, 2H), 6.63-6.78 (m, 1H), 6.23 (d, 1H)

Synthesis of Compound 254

For compound 254, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 254 in 23.6% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.07 (br. s., 1H), 8.47-8.78 (m, 1H), 7.81 (d,1H), 7.62 (m, 2H), 7.41 (m, 2H), 7.13-7.35 (m, 5H), 7.05 (s, 1H), 6.19(d, 1H), 4.34-4.49 (m, 2H)

Synthesis of Compound 255

For compound 255, general procedures K and J were used to obtaincompound 255 in 94.7% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.78 (d, 1H),7.45 (dd, 1H), 7.02-7.13 (m, 1H), 6.96 (s, 1H), 6.91-6.95 (m, 1H),6.82-6.91 (m, 1H), 6.20 (d, 1H), 3.79 (s, 3H)

Synthesis of Compound 256

For compound 256, compound 215 was used as an intermediate in generalprocedure J amide formation to form compound 256 in 39.1% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.88 (s, 1H), 8.07 (q, 1H), 7.76 (d, 1H), 7.24(m, 2H), 7.07 (m, 2H), 6.92 (s, 1H), 6.17 (d, 1H), 4.69 (spt, 1H), 2.70(d, 3H), 1.34 (d, 6H)

Synthesis of Compound 257

For compound 257, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 257 in 21.2% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 12.28 (s, 1H), 11.76 (br. s., 1H), 7.97 (d, 2H),7.89 (d, 1H), 7.69 (d, 2H), 7.50 (d, 2H), 7.20 (d, 1H), 6.28 (d, 1H)

Synthesis of Compound 258

For compound 258, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 258 in 41.6% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.25 (s, 1H), 8.19 (t, 1H), 7.80 (d, 1H), 7.64(m, 2H), 7.42 (m, 2H), 7.02 (s, 1H), 6.19 (d, 1H), 3.81-3.97 (m, 1H),3.68-3.81 (m, 1H), 3.50-3.68 (m, 1H), 3.10-3.38 (m, 2H), 1.67-1.96 (m,3H), 1.39-1.63 (m, 1H)

Synthesis of Compound 259

For compound 259, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 259 in 28.9% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 7.77 (d, 1H), 7.61 (m, 2H), 7.39 (m, 2H), 6.65(s, 1H), 6.18 (d, 1H), 3.52-3.63 (m, 4H), 2.66-2.77 (m, 4H)

Synthesis of Compound 260

For compound 260, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 260 in 51.9% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.27 (br. s., 1H), 7.95 (br. s., 1H), 7.77 (d,1H), 7.61 (m, 2H), 7.40 (m, 2H), 6.90 (s, 1H), 6.14 (d, 1H), 2.70 (d,3H)

Synthesis of Compound 261

For compound 261, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 261 in 25% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.30 (t, 1H), 7.76-7.86 (m, 1H), 7.62 (m, 2H),7.39 (m, 2H), 7.02 (s, 1H), 6.20 (d, 1H), 3.37-3.49 (m, 2H), 2.91 (br.s., 6H), 1.80 (br. s., 4H)

Synthesis of Compound 262

For compound 262, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 262 in 25.4% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 12.20 (br. s., 1H), 11.15 (br. s., 1H), 8.77 (t,1H), 7.83 (d, 1H), 7.63 (m, 2H), 7.47-7.59 (m, 1H), 7.36-7.47 (m, 3H),7.10-7.18 (m, 2H), 7.09 (s, 1H), 6.21 (d, 1H), 4.59-4.69 (m, 2H)

Synthesis of Compound 263

For compound 263, compound 215 was used as an intermediate in generalprocedure J amide formation to form compound 263 in 10% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.74 (br. s., 1H), 7.63 (d, 1H), 7.27 (m, 2H),7.05 (m, 2H), 6.82 (s, 1H), 6.43 (d, 1H), 5.90 (br. s., 2H), 4.54-4.67(m, 1H), 1.40 (d, 6H)

Synthesis of Compound 264

For compound 264, compound 215 was used as an intermediate in generalprocedure J amide formation to form compound 264 in 55% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.94 (br. s., 1H), 7.74 (d, 1H), 7.22 (m, 2H),7.05 (m, 2H), 6.73 (s, 1H), 6.17 (d, 1H), 4.57-4.80 (m, 1H), 3.06 (br.s., 6H), 1.33 (d, 6H)

Synthesis of Compound 265

For compound 265, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 265 in 19.3% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.75 (br. s., 1H), 9.91 (br. s., 1H), 7.78-7.99(m, 3H), 7.59-7.70 (m, 2H), 7.23-7.51 (m, 6H), 7.10-7.20 (m, 1H),6.99-7.08 (m, 2H), 6.71 (dd, 1H), 6.23 (d, 1H)

Synthesis of Compound 266

For compound 266, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 266 in 33.5% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 12.19 (br. s., 1H), 11.36 (br. s., 1H), 8.74 (br.s., 1H), 7.93 (m, 2H), 7.84 (d, 1H), 7.63 (m, 2H), 7.31-7.59 (m, 2H),7.02-7.19 (m, 3H), 6.20 (d, 1H), 4.53-4.70 (m, 2H)

Synthesis of Compound 267

For compound 267, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 267 in 25% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.55 (br. s., 1H), 9.91 (br. s., 1H), 7.83 (d,1H), 7.21-7.52 (m, 10H), 7.10-7.21 (m, 1H), 7.04 (d, 2H), 6.63-6.80 (m,1H), 6.10-6.33 (m, 1H)

Synthesis of Compound 268

For compound 268, compound 247 was used as an intermediate in generalprocedure J amide formation to form compound 268 in 46% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.29 (br. s., 1H), 8.45 (d, 1H), 7.82 (d, 1H),7.43-7.59 (m, 4H), 7.24-7.38 (m, 4H), 7.16-7.24 (m, 1H), 7.13 (s, 1H),6.20 (d, 1H), 5.09 (quin, 1H), 1.44 (d, 3H)

Synthesis of Compound 269

For compound 269, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 269 in 42% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.15 (br. s., 1H) 8.05 (br. s., 1H) 7.79 (d, 1H)7.30-7.52 (m, 4H) 6.94 (s, 1H) 6.18 (d, 1H) 2.71 (d, 3H)

Synthesis of Compound 270

For compound 270, compound 247 was used as an intermediate in generalprocedure J amide formation to form compound 270 in 34% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.30 (s, 1H), 7.98-8.15 (m, 1H), 7.81 (d, 1H),7.39-7.61 (m, 4H), 6.95 (s, 1H), 6.20 (d, 1H), 2.71 (d, 3H)

Synthesis of Compound 271

For compound 271, compound 247 was used as an intermediate in generalprocedure J amide formation to form compound 271 in 44.9% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 12.19 (br. s., 1H), 11.36 (s, 1H), 8.80 (t, 1H),7.84 (d, 1H), 7.31-7.61 (m, 6H), 7.11-7.19 (m, 2H), 7.10 (s, 1H), 6.22(d, 1H), 4.62 (d, 2H)

Synthesis of Compound 272

For compound 272, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 272 in 36% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.67 (s, 1H), 8.61 (dd, 1H), 7.80 (d, 1H),7.32-7.49 (m, 4H), 7.22 (dd, 1H), 7.05 (s, 1H), 6.74-6.89 (m, 3H), 6.19(d, 1H), 4.33-4.43 (m, 2H), 3.71 (s, 3H)

Synthesis of Compound 273

For compound 273, compound 247 was used as an intermediate in generalprocedure J amide formation to form compound 273 in 43% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.73 (br. s., 1H), 10.28 (s, 1H), 8.26-8.33 (m,1H), 8.02-8.16 (m, 1H), 7.90 (d, 1H), 7.47-7.68 (m, 6H), 7.38 (s, 1H),6.26 (d, 1H), 3.19 (s, 3H)

Synthesis of Compound 274

For compound 274, compound 255 was used as an intermediate in generalprocedure J amide formation to form compound 274 in 31.9% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.93 (br. s., 1H) 9.76 (s, 1H) 8.54-8.77 (m, 1H)7.78 (d, 1H) 7.19-7.40 (m, 6H) 7.03 (s, 1H) 6.92 (dd, 1H) 6.76 (d, 1H)6.70 (t, 1H) 6.18 (d, 1H) 4.42 (d, 2H)

Synthesis of Compound 275

For compound 275, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 275 in 26% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.75 (br. s., 1H), 9.90 (br. s., 1H), 7.78-8.03(m, 3H), 7.57-7.77 (m, 4H), 7.32-7.44 (m, 2H), 7.28 (br. s., 1H),7.05-7.17 (m, 1H), 6.90-7.05 (m, 4H), 6.12-6.34 (m, 1H)

Synthesis of Compound 276

For compound 276, compound 215 was used as an intermediate in generalprocedure J amide formation to form compound 276 in 28% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.07 (br. s., 1H), 9.42 (br. s., 1H), 8.38 (t,1H), 7.80 (d, 1H), 7.22 (m, 2H), 7.08 (m, 2H), 7.01 (d, 1H), 6.20 (d,1H), 4.69 (quin, 1H), 3.42-3.71 (m, 4H), 3.16-3.35 (m, 2H), 2.91-3.16(m, 2H), 1.77-2.07 (m, 4H), 1.34 (d, 6H)

Synthesis of Compound 277

For compound 277, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 277 in 31% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.62 (br. s., 1H), 10.26 (s, 1H), 8.22-8.32 (m,1H), 8.00-8.14 (m, 1H), 7.88 (d, 1H), 7.53-7.68 (m, 2H), 7.26-7.52 (m,5H), 6.25 (d, 1H), 3.19 (s, 3H)

Synthesis of Compound 278

For compound 278, compound 215 was used as an intermediate in generalprocedure J amide formation to form compound 278 in 30% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.40 (br. s., 1H), 10.24 (s, 1H), 8.14-8.24 (m,1H), 7.91-8.06 (m, 1H), 7.85 (d, 1H), 7.59 (dd, 1H), 7.36-7.45 (m, 1H),7.32 (s, 1H), 7.25 (m, 2H), 7.07 (m, 2H), 6.24 (d, 1H), 4.70 (quin, 1H),2.62 (s, 6H), 1.35 (d, 6H)

Synthesis of Compound 279

For compound 279, compound 215 was used as an intermediate in generalprocedure J amide formation to form compound 279 in 26% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.33 (br. s., 1H), 10.03 (br. s., 1H), 7.79-7.90(m, 2H), 7.54-7.66 (m, 1H), 7.35 (dd, 1H), 7.20-7.31 (m, 3H), 7.01-7.17(m, 3H), 6.23 (d, 1H), 4.70 (quin, 1H), 1.35 (d, 6H)

Synthesis of Compound 280

For compound 280, compound 255 was used as an intermediate in generalprocedure J amide formation to form compound 280 in 34.9% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.69 (s, 1H), 9.75 (br. s., 1H), 7.77 (d, 1H),7.35 (dd, 1H), 6.91 (dd, 1H), 6.85 (d, 1H), 6.71-6.79 (m, 1H), 6.69 (t,1H), 6.19 (d, 1H), 3.66 (br. s., 2H), 3.47 (br. s., 2H), 1.88 (br. s.,2H)

Synthesis of Compound 281

For compound 281, compound 215 was used as an intermediate in generalprocedure J amide formation to form compound 281 in 22.5% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 7.73 (d, 1H), 7.22 (m, 2H), 7.05 (m, 2H), 6.63(s, 1H), 6.17 (d, 1H), 4.56-4.79 (m, 1H), 3.54-3.64 (m, 4H), 2.66-2.79(m, 4H), 1.33 (d, 6H)

Synthesis of Compound 282

For compound 282, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 282 in 49% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.68 (br. s., 1H), 8.73 (br. s., 1H), 8.48 (dd,2H), 7.81 (d, 1H), 7.61 (m, 2H), 7.41 (m, 2H), 7.25 (d, 2H), 7.06 (s,1H), 6.19 (d, 1H), 4.43 (d, 2H)

Synthesis of Compound 283

For compound 283, compound 247 was used as an intermediate in generalprocedure J amide formation to form compound 283 in 52% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 12.28 (s, 1H), 11.69 (s, 1H), 7.86 (d, 1H), 7.58(s, 4H), 7.49 (d, 1H), 7.47 (br. s., 1H), 7.19 (d, 1H), 6.26 (d, 1H)

Synthesis of Compound 284

For compound 284, a similar modified general procedure K and J as forcompound 223 was followed. Compound 284 was obtained in 27% yield. ¹HNMR (300 MHz, DMSO-d6) ppm 12.54 (br. s., 1H), 8.24 (d, 1H), 7.66 (s,1H), 7.56 (d, 1H), 7.45 (m, 2H), 7.38 (m, 2H), 7.28 (d, 1H), 6.91 (d,1H), 3.88 (s, 3H)

Synthesis of Compound 285

For compound 285, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 285 in 33% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.14 (br. s., 1H), 8.19 (t, 1H), 7.79 (d, 1H),7.34-7.51 (m, 4H), 7.02 (s, 1H), 6.19 (d, 1H), 3.81-3.97 (m, 1H),3.68-3.81 (m, 1H), 3.52-3.67 (m, 1H), 3.11-3.38 (m, 2H), 1.68-1.97 (m,3H), 1.40-1.62 (m, 1H)

Synthesis of Compound 286

For compound 286, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 286 in 46% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.10 (t, 1H), 7.93 (m, 2H), 7.83 (d, 1H), 7.62(m, 2H), 7.00 (s, 1H), 6.20 (d, 1H), 3.22-3.38 (m, 2H), 2.40-2.60 (m,6H), 1.55-1.76 (m, 4H)

Synthesis of Compound 287

For compound 287, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 287 in 38% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 12.20 (br. s., 1H), 11.22 (br. s., 1H), 8.75-8.82(m, 1H), 7.83 (d, 1H), 7.29-7.60 (m, 6H), 7.04-7.19 (m, 3H), 6.21 (d,1H), 4.55-4.68 (m, 2H)

Synthesis of Compound 288

For compound 288, compound 215 was used as an intermediate in generalprocedure J amide formation to form compound 288 in 41.7% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.36 (s, 1H), 10.25 (s, 1H), 8.23-8.30 (m, 1H),8.02-8.12 (m, 1H), 7.85 (d, 1H), 7.56-7.65 (m, 2H), 7.32 (s, 1H), 7.27(m, 2H), 7.08 (m, 2H), 6.24 (d, 1H), 4.70 (spt, 1H), 3.19 (s, 3H), 1.35(d, 6H)

Synthesis of Compound 289

For compound 289, compound 247 was used as an intermediate in generalprocedure J amide formation to form compound 289 in 13% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.36 (s, 1H), 8.66 (t, 1H), 7.82 (d, 1H),7.45-7.60 (m, 4H), 7.14-7.36 (m, 5H), 7.06 (s, 1H), 6.20 (d, 1H), 4.42(d, 2H)

Synthesis of Compound 290

For compound 290, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 290 in 18% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.70 (br. s., 1H), 10.26 (s, 1H), 8.24-8.30 (m,1H), 8.01-8.14 (m, 1H), 7.88 (d, 1H), 7.53-7.69 (m, 4H), 7.43 (m, 2H),7.34-7.38 (m, 1H), 6.25 (d, 1H), 3.19 (s, 3H)

Synthesis of Compound 291

For compound 291, compound 255 was used as an intermediate in generalprocedure J amide formation to form compound 291 in 56% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.31 (br. s., 1H), 10.04 (br. s., 1H), 9.75 (s,1H), 7.86-7.88 (m, 1H), 7.84 (d, 1H), 7.59 (d, 1H), 7.37 (dd, 1H), 7.35(dd, 1H), 7.28 (s, 1H), 7.05-7.15 (m, 1H), 6.88-6.99 (m, 1H), 6.77 (d,1H), 6.70-6.74 (m, 1H), 6.23 (d, 1H)

Synthesis of Compound 292

For compound 292, compound 215 was used as an intermediate in generalprocedure J amide formation to form compound 292 in 35.3% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 12.20 (br. s., 1H), 10.68 (br. s., 1H), 8.80 (t,1H), 7.79 (d, 1H), 7.32-7.62 (m, 2H), 7.25 (m, 2H), 6.99-7.17 (m, 5H),6.19 (d, 1H), 4.64-4.74 (m, 1H), 4.56-4.64 (m, 2H), 1.32 (d, 6H)

Synthesis of Compound 293

For compound 293, compound 213 was used as an intermediate in generalprocedure J amide formation to form compound 293 in 32.6% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.39 (br. s., 1H), 7.99-8.15 (m, 1H), 7.94 (m,2H), 7.83 (d, 1H), 7.62 (m, 2H), 6.96 (s, 1H), 6.21 (d, 1H), 2.71 (d,3H)

Synthesis of Compound 294

For compound 294, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 294 in 30.7% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 12.25 (br. s., 1H), 11.59 (br. s., 1H), 7.85 (d,1H), 7.36-7.57 (m, 6H), 7.19 (d, 1H), 6.26 (d, 1H)

Synthesis of Compound 295

For compound 295, compound 225 was used as an intermediate in generalprocedure J amide formation to form compound 295 in 18% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.67 (br. s., 1H), 10.16 (br. s., 1H), 8.19 (s,1H), 7.95 (br. s., 1H), 7.87 (d, 1H), 7.63 (m, 2H), 7.47-7.55 (m, 2H),7.44 (m, 3H), 7.20-7.39 (m, 2H), 6.23 (d, 1H)

Synthesis of Compound 296

For compound 296, compound 216 was used as an intermediate in generalprocedure J amide formation to form compound 296 in 31.9% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.20 (s, 1H), 8.43 (d, 1H), 7.81 (d, 1H),7.25-7.47 (m, 8H), 7.15-7.25 (m, 1H), 7.12 (s, 1H), 6.19 (d, 1H), 5.10(quin, 1H), 1.44 (d, 3H)

Synthesis of Compound 297

For compound 297, compound 215 was used as an intermediate in generalprocedure J amide formation to form compound 297 in 35.8% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.25 (s, 1H), 9.90 (s, 1H), 7.83 (d, 1H),7.60-7.70 (m, 1H), 7.30-7.41 (m, 1H), 7.19-7.30 (m, 3H), 7.01-7.19 (m,3H), 6.22 (d, 1H), 4.70 (quin, 1H), 3.81 (s, 3H), 1.35 (d, 6H)

Synthesis of Compound 298

Compound 298 was prepared by mixing a methoxy intermediate in anhydrousDCM and 2 eq of BBr₃ at 0° C. After the reaction was complete (about 1-2hours), it was washed with saturated NaHCO₃ several times until neutral.Organic solution was dried (sodium sulfate) and evaporated. Compound 298was isolated by pre-TLC to give pure product (82% yield) as a whitesolid. MS-ESI: m/z=202.1 [M+1]⁺

Synthesis of Compound 299

Similar to the synthesis of compound 298, compound 299 was prepared in87% yield as a white solid. MS-ESI: m/z=202.3 [M+1]⁺

Synthesis of Compound 300

Following general procedure A, compound 300 was prepared in 42% yield asa white solid. MS-ESI: m/z=204.3 [M+1]⁺

Synthesis of Compound 301

Following general procedure A, compound 301 was prepared in 9% yield asa solid. MS-ESI: m/z=204.3 [M+1]⁺

Synthesis of Compound 302

Following general procedure A, compound 302 was prepared in 27.3% yieldas a white solid. MS-ESI: m/z=220.3 [M+1]⁺; 222.2 [M+3]⁺

Synthesis of Compound 303

Following general procedure A, compound 303 was prepared in 20% yield asa white solid. MS-ESI: m/z=216.3 [M+1]⁺

Synthesis of Compound 304

Following general procedure A, compound 304 was prepared in 66% yield asa white solid. MS-ESI: m/z=216.3 [M+1]⁺

Synthesis of Compound 305

Following general procedure A, compound 305 was prepared in 50% yield asa yellowish solid. MS-ESI: m/z=216.3 [M+1]⁺

Synthesis of Compound 306

Following general procedure A, compound 306 was prepared in 43% yield asan oil. MS-ESI: m/z=244.0 [M+1]⁺

Synthesis of Compound 307

Following general procedure A, compound 307 was prepared in 81% yield asan oil. MS-ESI: m/z=244.1 [M+1]⁺

Synthesis of Compound 308

Following general procedure A, compound 308 was prepared in 87% yield asa reddish brown solid. MS-ESI: m/z=244.2 [M+1]⁺

Synthesis of Compound 309

Following general procedure A, compound 309 was prepared in 80% yield asa yellowish solid. MS-ESI: m/z=234.3 [M+1]⁺

Synthesis of Compound 310

Following general procedure A, compound 310 was prepared in 85% yield asa light yellow solid. MS-ESI: m/z=248.2 [M+1]⁺

Synthesis of Compound 311

Following general procedure A, compound 311 was prepared in 76% yield asa white solid. MS-ESI: m/z=250.2 [M+1]⁺

Synthesis of Compound 312

Following general procedure A, compound 312 was prepared in 22% yield asa white solid. MS-ESI: m/z=266.2 [M+1]⁺

Synthesis of Compound 313

Following general procedure A, compound 313 was prepared in 25% yield asa light yellow solid. MS-ESI: m/z=230.2 [M+1]⁺

Synthesis of Compound 314

Following general procedure A, compound 314 was prepared in 27% yield asa colorless oil. MS-ESI: m/z=242.2 [M+1]⁺

Synthesis of Compound 315

Following general procedure A, compound 315 was prepared in 32% yield asa white solid. MS-ESI: m/z=240.1 [M+1]⁺

Synthesis of Compound 316

Following general procedure A, compound 316 was prepared in 92% yield asa light yellow solid. MS-ESI: m/z=202.2 [M+1]⁺

Synthesis of Compound 317

Following general procedure A, compound 317 was prepared in 28% yield asa white solid. MS-ESI: m/z=186.2 [M+1]⁺

Synthesis of Compound 318

Compound 318 was prepared as follows.

Following general procedure A, the intermediate compound was prepared in78% yield as a white solid. MS-ESI: m/z=278.1 [M+1]⁺ To a solution ofthe intermediate (3.5 g, 10.8 mmol) in methanol (200 ml) was added Pd/C(300 mg) catalyst under N₂ atmosphere, and then stirred for 2 h under H₂atmosphere (1 atm, 25° C.). The catalyst was filtered off through thecelite pad, and the filtrate was concentrated in vacuo to give compound318 (2.2 g, 93% yields) as a white solid. MS-ESI: m/z=188.2 [M+1]⁺

Synthesis of Compound 319

Following general procedure A, compound 319 was prepared in 85% yield asa white solid. MS-ESI: m/z=206.3 [M+1]⁺

Synthesis of Compound 320

Following general procedure A, compound 320 was prepared in 84% yield asa white solid. MS-ESI: m/z=240.3 [M+1]⁺

Synthesis of Compound 321

Following general procedure A, compound 321 was prepared in 79% yield asa solid. MS-ESI: m/z=206.2 [M+1]⁺; 208.2 [M+3]⁺

Synthesis of Compound 322

Compound 322 was synthesized as follows.

To a solution Br-substitution-1-Phenyl-1H-pyridin-2-one (1 eq), theappropriate boromic acid (1.2 eq), potassium phosphate (3.5 eq) andtricyclohexylphosphine (0.1 eq) in toluene/water (2:/1, V:V) under anitrogen atmosphere was added palladium acetate (0.05 eq). The mixturewas heated to 100° C. for 2-3 h, and then cooled to room temperature,water was added and the mixture was extracted with EtOAc, the combinedorganics were washed with brine and water, dried over anhydrous Na₂SO₄,and concentrated in vacuo. The residue was purified by pre-TLC to affordthe desired compound 322 in 70% yield as a pink solid. MS-ESI: m/z=212.2[M+1]⁺

Synthesis of Compound 323

Similar to compound 322, compound 323 was prepared in 60% yield as ayellow solid. MS-ESI: m/z=274.3 [M+1]⁺

Synthesis of Compound 324

Compound 324 was synthesized as follows. To compound 318 (2.2 g, 11.8mmol) in DCM (120 ml) was added triethylanine (1.7 g, 16.8 mmol) at −78°C., followed by the addition of trifluoromethanesulfonic anhydride (4.76g, 16.9 mmol). The resulting mixture was stirred at −78° C. for 15 minand quenched with ammonium chloride solution (10 ml). After warming toroom temperature, water (30 ml) and DCM (50 ml) were added andseparated. The intermediate triflate was obtained by washing the crudewith methanol and gave 2.12 g pure compound in 90% yield. A solution ofthe intermediate triflate (trifluoro-methanesulfonic acid2-oxo-1-phenyl-1,2-dihydro-pyridin-4-yl ester) (0.79 mmol) andtetrakis(triphenylphosphine)palladium (0.011 g, 0.0095 mmol) indimethoxyethane (1 ml) was stirred at room temperature for 15 minfollowed by the addition of the solution arylboronic acid (0.21 mmol) indimethoxyethane (1 ml) and 2M sodium carbonate (1 ml). The resultingmixture was refluxed for 14 hr and cooled down to room temperature.Water and ethyl acetate were added. After separation, the aqueous layerwas extracted with ethyl acetate. The combined ethyl acetate solutionwas dried (Na₂SO₄) and filtered, and the filtrate was concentrated invacuo to dryness. Compound 324 was obtained in 51.6% yield as a solid.MS-ESI: m/z=248.3 [M+1]⁺

Synthesis of Compound 325

Similar to compound 324, compound 325 was prepared in 60.2% yield as asolid. MS-ESI: m/z=212.2 [M+1]⁺

Synthesis of Compound 326

Following general procedure A, compound 326 was prepared in 15% yield.MS-ESI: m/z=212.3 [M+1]⁺

Synthesis of Compound 327

Compound 327 was prepared as follows.

A mixture of 2,6-dibromopyridine (4 g, 17 mmol), potassium t-butoxide(20 g, 0.27 mol), and redistilled t-butyl alcohol (100 ml) was refluxedovernight. After cooling, the solvent was removed in vacuo, ice/waterwas carefully added, and the aqueous layer was extracted with chloroform(100 ml×2), which removed the unreacted staring material. The aqueouslayer was acidified with 3 N HCl, extracted with chloroform (100 ml×2),washed with brine, dried over anhydrous Na₂SO₄ and concentratedaffording pure 6-bromo-2-pyridone (2.5 g, 85% yield) as a white solid.Intermediate 3 was prepared following general procedure A in 73% yield.Intermediate 3 was then reacted with the appropriate boronic acid,Pd(OAc)₂, PCy₃, K₃PO₄ at 100° C. to afford compound 327 in 40% yield asan oil. MS-ESI: m/z=248.3 [M+1]⁺

Synthesis of Compound 328

Similar to compound 327, compound 328 was prepared in 9.48% yield as anoil. MS-ESI: m/z=212.2 [M+1]⁺

Synthesis of Compound 329

Following general procedure A, compound 329 was prepared in 90% yield asa white solid. MS-ESI: m/z=298.3 [M+1]⁺

Synthesis of Compound 330

Following general procedure A, compound 330 was prepared in 75% yield asa yellowish solid. MS-ESI: m/z=230.4 [M+1]⁺

Synthesis of Compound 331

Following general procedure A, compound 331 was prepared in 81% yield asan oil. MS-ESI: m/z=262.1 [M+1]⁺

Synthesis of Compound 332

Following general procedure A, compound 332 was prepared in 80% yield asa solid. MS-ESI: m/z=276.2 [M+1]⁺

Synthesis of Compound 333

Following general procedure F, compound 333 was prepared in 65% yield togive a yellowish solid. MS-ESI: m/z=280.1 [M+1]⁺

Synthesis of Compound 334

Following general procedure F, compound 334 was prepared in 59% yield.MS-ESI: m/z=256.2 [M+1]⁺, 258.2. [M+3]⁺

Synthesis of Compound 335

Compound 335 was prepared as follows.

A mixture of compound 1 (200 mg, 1.3 mmol) in AcOH (4 ml) was added HBr(aq. 40%, 1 ml), then heated to reflux for 2 h. The compound 2 wasobtained by evaporated in vacuo (160 mg, 90%). To a mixture of compound2 (160 mg, 1.2 mmol), phenylboronic acid (293 mg, 2.4 mmol) and Cu(OAc)₂(36 mg, 0.2 mmol) in DCM, pyridine (190 mg, 2.4 mmol) was added slowly.After the suspension was stirred overnight at room temperature, it waschecked by TLC and the starting material was completely vanished, andthen washed with saturated NaHCO₃. The DCM layer was dried over sodiumsulfate, and evaporated to obtain the crude product. The crude productwas purified by preparative TLC to afford the compound 3 (110 mg, 43%).A mixture of compound 3 (110 mg, 0.5 mmol) in DAST (2.5 ml) was heatedto 80° C. for 4 h. The reaction mixture was extracted by DCM andsaturated NaHCO₃, and the crude product was purified by preparative TLCto give compound 335 (40 mg, 34% yield) as yellow solid. MS-ESI:m/z=236.3 [M+1]⁺

Synthesis of Compound 336

Similar to the synthesis of compound 91, compound 336 was prepared in63% yield as a white solid. MS-ESI: m/z=262.1 [M+1]⁺

Synthesis of Compound 337

Similar to the synthesis of compound 91, compound 337 was prepared in70% yield to give a white solid. MS-ESI: m/z=238.2 [M+1]⁺, 240.3 [M+3]⁺

Synthesis of Compound 338

Compound 338 was synthesized as follows.

A mixture of compound 2 (1 g, 5 mmol) andtrimethyl-trifluoromethyl-silane (3.5 ml, 2M in THF, 7 mmol) in THF (20ml) cooled to 0° C. in an ice bath was treated with tetrabutylammoniumfluoride (0.25 ml, 1 m in THF, 0.25 mmol) under nitrogen atmosphere at0° C. for 30 min. The mixture was raised to room temperature and stirred24 h. Then 1 M HCl (50 ml) was added and the mixture was stirredovernight. The aqueous layer was extracted with EtOAc (50 ml×2) and theorganics was concentrated. The desired product was separated by columnarchromatography to give compound 338 (0.94 g, 70% yields) as yellowsolid. MS-ESI: m/z=270.2 [M+1]⁺

Synthesis of Compound 339

Compound 339 was prepared from compound 338 as follows. Compound 338 (50mg, 0.19 mmol) and manganese dioxide (165 mg, 1.9 mmol) were stirredovernight at room temperature in DCM (5 ml). The reaction was detectedby TLC. Upon completion, the crude mixture was filtered through a pad ofcelite and the filtrate was concentrated. The desired compound wasisolated by washing the crude with PE to give pure intermediate product(36 mg, 70% yields) as a white solid. A mixture of this intermediate(100 mg, 0.37 mmol) and trimethyl-trifluoromethyl-silane (0.27 ml, 2 Min THF, 0.54 mmol) in THF (2 ml) cooled to 0° C. in an ice bath istreated with tetrabutylammonium fluoride (0.02 ml, 1 M in THF, 0.02mmol) under nitrogen atmosphere at 0° C. for 30 min. The mixture wasraised to room temperature and stirred 24 h. Then 1 M HCl (20 ml) wasadded and the mixture was stirred overnight. The aqueous layer wasextracted with EtOAc (30 ml×3) and the organics was concentrated. Thedesired product was separated out by washing the crude with EtOAc togive compound 339 (54 mg, 43% yield) as a white solid. MS-ESI: m/z=338.2[M+1]⁺

Synthesis of Compound 340

Compound 340 was prepared from compound 338 as follows. Compound 338 (50mg, 0.19 mmol) in dry DCM (1 ml) was added at the temperature of −78° C.under N₂ atmosphere to a solution of DAST (34 mg, 0.21 mmol) in DCM (1ml). The mixture was stirred at −78° C. for 2 h, and then warmed to roomtemperature overnight. The reaction mixture was diluted with DCM (20ml), and poured into saturated NaHCO₃ (30 ml). Organic phase wasseparated and dried over Na₂SO₄ and concentrated in vacuo. Desiredcompound was isolated by thin-layer chromatography to give pure compound340 (16 mg, 30% yields) as a yellowish solid. MS-ESI: m/z=272.2 [M+1]⁺

Synthesis of Compound 341

Compound 341 was prepared from compound 338 as follows. Compound 338 (50mg, 0.19 mmol) and manganese dioxide (165 mg, 1.9 mmol) were stirredovernight at room temperature in DCM (5 ml). The reaction was detectedby TLC. Upon completion, the crude mixture was filtered through a pad ofcelite and the filtrate was concentrated. The desired compound wasisolated by washing the crude with PE to give pure intermediate product(36 mg, 70% yield) as a white solid.

To a suspension of methyltriphosphonium bromide (336 mg, 0.96 mmol) intetrahydrofuran (16 ml) maintained at 0° C. was added n-butyllithium(0.4 ml, 2.5 M solution in THF). The resulting solution was stirred forfifteen minutes prior to the addition of a solution of this intermediate(200 mg, 0.76 mmol) in tetrahydrofuran (10 ml). The reaction mixture wasstirred for about 1 h before quenching by dilution with water. Thesecond intermediate product was extracted into EA and the combinedorganic layers were evaporated under reduced pressure, the secondintermediate product was isolated by TLC (150 mg, 76% yield).1-phenyl-5-(3,3,3-trifluoroprop-1-en-2-yl)pyridine-2(1H)-one (the secondintermediate product) (100 mg, 0.38 mmol) in C₂H₅OH (8 ml) was addedPd/C (10 mg) under N₂. The reaction mixture was stirred for 2 h underH₂, then filtered, extracted by DCM, washed by brine, dried by Na₂SO₄.Compound 341 was isolated by TLC (79 mg, 79% yield) as oil. MS-ESI:m/z=268.3 [M+1]⁺

Synthesis of Compound 342

Compound 342 was prepared from compound 338 as follows. Compound 338 (50mg, 0.19 mmol) and manganese dioxide (165 mg, 1.9 mmol) were stirredovernight at room temperature in DCM (5 ml). The reaction was detectedby TLC. Upon completion, the crude mixture was filtered through a pad ofcelite and the filtrate was concentrated. The desired compound wasisolated by washing the crude with PE to give pure intermediate product(36 mg, 70% yield) as a white solid. Then, following general procedureD, compound 342 was prepared in 64% yield as a white solid. MS-ESI:m/z=290.3 [M+1]⁺

Synthesis of Compound 343

Compound 343 was prepared as follows.

Intermediate 3 was prepared thus. To a solution of compound 1 (3.0 g, 16mmol), compound 2 (2.5 g, 21 mmol), K₃PO₄ (12.5 g, 57 mmol) intoluene/water (60 ml/3 ml) under a nitrogen atmosphere was addedPd(PPh₃)₄ (2.0 g, 1.6 mmol). The mixture was heated to reflux for 3 hand then cooled to room temperature. Water was added and the mixtureextracted with EtOAc, the combined organics were washed with brine,dried over Na₂SO₄ and concentrated in vacuo. The product was isolated bycolumn chromatography afforded the compound 3. (2.1 g, 69%).Intermediate 3 (2.0 g, 11 mmol) in HBr (aq. 40%)/EtOH (20 ml/4 ml) washeated to reflux for 2 h, the reaction was monitored by TLC, whencompleted, the mixture was cooled to r.t. The reaction mixture wasneutralized by NaHCO₃, then extracted with EtOAc several times. Thecombined organics was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to afford the compound 4 (1.7 g, 91%) Followinggeneral procedure A, compound 343 was prepared from intermediate 4 in50% as an oil. MS-ESI: m/z=306.0 [M+1]⁺

Synthesis of Compound 344

Similar to compound 343, compound 344 was prepared in 15% yield as awhite solid. MS-ESI: m/z=277.9 [M+1]⁺

Synthesis of Compound 345

Similar to compound 343, compound 345 was prepared in 60% yield as awhite solid. MS-ESI: m/z=281.9 [M+1]⁺

Synthesis of Compound 346

Similar to compound 343, compound 346 was prepared in 90% yield as ayellowish solid. MS-ESI: m/z=305.9 [M+1]⁺

Synthesis of Compound 347

Similar to compound 343, compound 347 was prepared in 85% yield as asolid. MS-ESI: m/z=278.0 [M+1]⁺

Synthesis of Compound 348

Similar to compound 343, compound 348 was prepared in 50% yield as awhite solid. MS-ESI: m/z=331.8 [M+1]⁺

Synthesis of Compound 351

Following general procedure A, compound 351 was prepared in 55% yield asa white solid. MS-ESI: m/z=269.9 [M+1]⁺

Synthesis of Compound 352

Following general procedure A, compound 352 was prepared in 70% yield asa reddish liquid. MS-ESI: m/z=298 [M+1]⁺

Synthesis of Compound 353

Following general procedure A, compound 353 was prepared in 85% yield asa white solid. MS-ESI: m/z=270.0 [M+1]⁺

Synthesis of Compound 354

Following general procedure A, compound 354 was prepared in 78% yield asa solid. MS-ESI: m/z=273.9 [M+1]⁺

Synthesis of Compound 355

Following general procedure A, compound 355 was prepared in 68% yield asa white solid. MS-ESI: m/z=244.1 [M+1]⁺

Synthesis of Compound 356

Following general procedure A, compound 356 was prepared in 65% yield asa white solid. MS-ESI: m/z=270.0 [M+1]⁺

Synthesis of Compound 357

Following general procedure F, compound 357 was prepared in 68% yield.MS-ESI: m/z=305.9 [M+1]⁺

Synthesis of Compound 358

Similar to the synthesis of compound 100, compound 358 was prepared in80% yield as a white solid. MS-ESI: m/z=300.2 [M+1]⁺

Synthesis of Compound 359

Compound 359 was prepared as follows.

A mixture of reagent 1 (0.5-1 mmol, 1 eq.), boronic acids 2 (2 eq.),copper(II) acetate (0.4-0.6 eq.), pyridine (2 eq.) and molecular sieves4A in dichloromethane (5 ml/1 mmol reagent 1) was stirred for overnightat the room temperature opened to the air. The reactions were monitoredby TLC, and when found to be completed washed with saturated sodiumbicarbonate with EDTA and dried over sodium sulfate. Compounds 3 wereisolated by pre-TLC (using EA/PE as solvent). Reagent 3 (0.3-0.5 mmol, 1eq.) was dissolved in acetonitrile (3 mL/1 mmol reagent 3), DAST (2 eq.)was added slowly at room temperature. The resulting solution was stirredat 80° C. in a capped plastic tube overnight. After cooling to roomtemperature, it was diluted with DCM, washed with aqueous solution ofsaturated sodium bicarbonate, water and brine, dried over Na₂SO₄,concentrated to give a residue, which was purified by pre-TLC (usingEA/PE as solvent) to give target compound. Following this procedure,compound 359 was prepared in 13.9% yield as a white solid. ¹H NMR (400MHz, CDCl₃): 2.98 (s, 6H); 3.323˜6.341 (t, J=5.6 Hz, 1H); 6.460˜6.599(d, J=55.6 Hz, 1H); 6.639˜6.657 (d, J=7.2 Hz, 2H); 6.765˜6.790 (d,J=10.0 Hz, 2H); 7.314˜7.353 (t, J=8.0 Hz, 1H); 7.446˜7.464 (d, J=7.2 Hz,1H) MS-ESI: m/z=265.1 [M+1]⁺

Synthesis of Compound 360

Similar to preparation of compound 359, compound 360 was prepared in19.7% yield as a white solid. ¹H NMR (400 MHz, CDCl₃): 6.278˜6.647 (m,2H); 6.679 (s, 1H); 7.314˜7.343 (t, J=11.6 Hz, 2H); 7.395˜7.419 (d,J=9.6 Hz, 1H); 7.459˜7.498 (q, J=15.6 Hz, 2H) MS-ESI: m/z=256.3 [M+1]⁺

Synthesis of Compound 361

Similar to preparation of compound 359, compound 361 was prepared in19.8% yield as a white solid. ¹H NMR (400 MHz, CDCl₃): 1.350˜1.371 (d,J=8.4 Hz, 6H), 4.554˜4.594 (t, J=16 Hz, 1H), 6.274˜6.643 (m, 2H); 6.777(s, 1H); 6.673 (s, 1H); 6.950˜6.980 (q, J=12 Hz, 2H); 7.242˜7.272 (q,J=12 Hz, 2H), 7.422˜7.446 (d, J=9.6 Hz, 1H) MS-ESI: m/z=280.2 [M+1]⁺

Synthesis of Compound 362

Similar to preparation of compound 359, compound 362 was prepared in20.1% yield as a white solid. ¹H NMR (400 MHz, CDCl₃): 6.289˜6.697 (m,2H); 6.679 (s, 1H); 7.410˜7.435 (d, J=10 Hz, 1H); 7.531˜7.569 (d, J=15.2Hz, 2H); 7.770˜7.812 (d, J=16.8 Hz, 2H) MS-ESI: m/z=290.3 [M+1]⁺

Synthesis of Compound 363

Similar to preparation of compound 359, compound 363 was prepared in20.1% yield as a white solid. ¹H NMR (400 MHz, CDCl₃): 3.847 (s, 1H),6.320˜6.596 (m, 2H); 6.758 (s, 1H); 6.979˜7.018 (m, 2H); 7.273˜7.303 (m,2H); 7.420˜7.438 (d, J=7.2 Hz, 1H) MS-ESI: m/z=252.3 [M+1]⁺

Synthesis of Compound 364

Similar to preparation of compound 359, compound 364 was prepared in27.8% yield as a white solid. ¹H NMR (400 MHz, CDCl₃): 6.335-6.612 (m,2H); 6.784-6.786 (d, J=0.8 Hz 1H); 7.349˜7.372 (t, J=9.2 Hz, 2H);7.419˜7.449 (m, 3H) MS-ESI: m/z=306.3 [M+1]⁺

Synthesis of Compound 367

Similar to preparation of compound 359, compound 367 was prepared in7.8% yield as a white solid. ¹H NMR (400 MHz, CDCl₃): 1.907˜1.998 (t,J=36.4 Hz, 3H), 6.338˜6.614 (m, 2H); 6.780 (s, 1H); 7.436˜7.601 (m, 5H)MS-ESI: m/z=286.3 [M+1]⁺

Synthesis of Compound 368

Similar to preparation of compound 359, compound 368 was prepared in10.2% yield as a white solid. ¹H NMR (400 MHz, CDCl₃): 1.905˜1996 (t,J=36.4 Hz, 3H), 6.338˜6.614 (m, 2H); 6.788 (s, 1H); 7.423˜7.466 (t,J=17.2 Hz, 3H), 7.646˜7.668 (d, J=8.8 Hz, 2H) MS-ESI: m/z=286.3 [M+1]⁺

Synthesis of Compound 371

Similar to the synthesis of compound 95, compound 371 was prepared in82% yield as a white solid. MS-ESI: m/z=246.2 [M+1]⁺, 248.2 [M+3]⁺

Synthesis of Compound 372

Similar to the synthesis of compound 95, compound 372 was prepared in86% yield as a white solid. MS-ESI: m/z=270.0 [M+1]⁺

Synthesis of Compound 373

Similar to the synthesis of compound 95, compound 373 was prepared in88% yield as a white solid. MS-ESI: m/z=242.3 [M+1]⁺

Synthesis of Compound 374

Similar to the synthesis of compound 95, compound 374 was prepared in60% yield as a white solid. MS-ESI: m/z=296.3 [M+1]⁺

Synthesis of Compound 376

Compound 376 was prepared as follows.

5-bromo-2-methoxypyridine (0.66 g, 3.49 mmol) and1,3,5-trimethyl-1h-pyrazole-4-boronic acid pinacol ester (0.99 g, 4.19mmol) were dissolved in a degassed DME/H₂O mixture (14 mL, 10:1 ratio).Solid Na₂CO₃ (1.1 g, 10.47 mmol) was added, followed by Pd(PPh₃)₄ (0.2g, 0.17 mmol). The reaction mixture was heated at 80° C. for 18 h. Waterwas added until complete dissolution of the residual carbonate and thesolution was stirred for additional 6h at the same temperature. Theorganic layer was separated and evaporated under reduced pressure andthe resulting crude mixture was purified by flash chromatography (SiO₂;DCM/MeOH 20:1). 440 mg (66% yield) of pure product were obtained as apale yellow solid. MS-ESI: m/z=218.3[M+1]⁺5-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2(1H)-one (0.44 g, 2.3mmol) was dissolved in EtOH (3 mL). An excess of 48% HBr aqueoussolution (10 mL) was added and the reaction was heated at 90° C. for 24h. The solvent was removed under reduced pressure and the crude waspurified by flash chromatography (SiO₂; AcOEt to AcOEt/MeOH 3.5:1). 400mg (92% yield) of pure intermediate product were obtained as anoff-white foam.

Following general procedure H1A, compound 376 was prepared from thisintermediate in 58% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.39-7.57 (m,7H), 6.54 (d, 1H), 3.66 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H)

Synthesis of Compound 377

Similar to the procedure for compound 376, compound 377 was prepared in30% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 10.11 (s, 1H), 7.73 (dd, 1H),7.51-7.63 (m, 1H), 7.47 (dd, 1H), 7.42 (dd, 1H), 7.39 (d, 1H), 7.03-7.15(m, 1H), 6.53 (d, 1H), 3.66 (s, 3H), 2.19 (s, 3H), 2.10 (s, 3H), 2.05(s, 3H)

Synthesis of Compound 378

Compound 378 was prepared as follows.

2-bromo pyrimidine (0.55 g, 3.49 mmol) and 2-methoxy-5-pyridineboronicacid (0.53 g, 3.49 mmol) were dissolved in a degassed mixture of DME/H₂O(11 mL, 10:1 ratio). Solid K₂CO₃ (1.4 g, 10.47 mmol) was added, followedby Pd(PPh₃)₄ (0.2 g, 0.17 mmol). The reaction mixture was heated at 90°C. for 18 h. The organic layer was separated and evaporated undervacuum. The resulting crude was purified by flash chromatography (SiO₂;Pet. Ether/AcOEt 1:1). 420 mg (65% yield) of pure product were obtainedas a pale yellow solid. MS-ESI: m/z=188[M+1]⁺2-(6-methoxypyridin-3-yl)pyrimidine (0.78 g, 4 mmol) was dissolvedin EtOH (5 mL). An excess of 48% HBr aqueous solution (10 mL) was addedand the reaction was heated at 90° C. for 24 h. The solvent was removedunder reduced pressure and the residual hydrobromic acid was stripped atreduced pressure, at 40° C. The resulting off white solid was used inthe next step without further purification. MS-ESI: m/z=174 [M+1]⁺

Following general procedure H1A, compound 378 was prepared from thisintermediate in 30% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.82 (d, 2H)8.56 (dd, 1H) 8.41 (dd, 1H) 7.70 (m, 2H) 7.51-7.60 (m, 2H) 7.38 (t, 1H)6.66 (dd, 1H)

Synthesis of Compound 379

Compound 379 was prepared as follows.

The 5-iodo-1-arylpyridin-2(1H)-one (1 eq), the boronic acid (1.2 eq) andK₂CO₃ (3 eq) were dissolved in a 10:1 mixture of DME/H₂O (4 ml/mmol).The solution was degassed by bubbling N₂ for 15 min and then Pd(PPh₃)₄(0.05 eq) was added. The reaction mixture was heated at 90° C. for 18 h,after which time, BOC protecting group was completely cleaved. Mixturewas cooled at room temperature, diluted with AcOEt and filtered on acelite plug. The filtrate was washed with brine. The separated organicphase was dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was purified by column chromatography (EtOAc:Hexanes3:7 to 1:1) to afford compound 379 as a pale yellow solid (11% yield).¹H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 7.98 (s, 2H), 7.80-7.87 (m,1H), 7.69 (t, 1H), 7.56-7.64 (m, 1H), 7.10 (ddd, 1H), 6.54 (dd, 1H),2.06 (s, 3H)

Synthesis of Compound 380

Compound 380 was prepared as follows.

Following the standard procedure for Suzuki coupling the intermediatewas obtained by reaction of 3 g (16 mmol) of 5-bromo-2-methoxy-pyridine.After purification (SiO₂; Hexanes:EtOAc 9:1) 1.4 g (31% yield) of pureproduct were obtained as white solid.2-methoxy-5-(4-methoxyphenyl)pyridine (1.4 g, 4.96 mmol) was dissolvedin HBr 48% (12 ml) and EtOH (6 ml) and the solution was heated at refluxfor 24 h. After evaporation of volatiles the desired pyridone wasobtained as white solid (0.99 g, quantitative yield).

Following general procedure H1A, compound 380 was prepared in 40% yield.¹H NMR (300 MHz, DMSO-d6) ppm 7.85-7.98 (m, 2H), 7.66 (m, 2H), 7.47-7.61(m, 4H), 6.97 (m, 2H), 6.51-6.65 (m, 1H), 3.77 (s, 3H)

Synthesis of Compound 381

Compound 381 was prepared as follows.

The product was obtained by reaction of 963 mg (6.3 mmol) of2-methoxy-pyridine-5-boronic acid. After purification (SiO₂;Hexanes:EtOAc 1:1) 747 mg (65% yield) of pure product were obtained aswhite solid. 2-(6-methoxypyridin-3-yl)pyrimidine (747 mg) was dissolvedin HBr 48% (10 ml) and EtOH (5 ml) and the solution was heated at refluxovernight. After evaporation of volatiles the desired pyridone wasobtained as white solid (1.016 g, quantitative yield).

Following general procedure H1A, compound 381 was prepared from thisintermediate in 14% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.81 (d, 2H),8.53 (dd, 1H), 8.40 (dd, 1H), 7.42-7.65 (m, 5H), 7.37 (dd, 1H), 6.65 (d,1H)

Synthesis of Compound 382

Similar to compound 381, compound 382 was prepared in 33% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.16 (s, 1H), 8.81 (d, 2H), 8.53 (dd, 1H), 8.39(dd, 1H), 7.76-7.84 (m, 1H), 7.55-7.66 (m, 1H), 7.47 (dd, 1H), 7.37 (dd,1H), 7.18 (ddd, 1H), 6.64 (dd, 1H), 2.07 (s, 3H)

Synthesis of Compound 383

Compound 383 was prepared as follows.

5-iodo-1-phenyl-1H-pyridin-2-one (0.34 g, 1.13 mmol) was dissolved indry and degassed toluene 5 mL). The catalyst was then added (0.065 g,0.057 mmol) and the mixture was stirred for 10 minutes.1-methyl-4-(tributylstannyl)-3-(trifluoromethyl)-1H-pyrazole (0.49 g,1.13 mmol) was added and the reaction was heated at 90° C. for 18 hunder nitrogen atmosphere. Conc. NH₄OH was added. The solvent wasremoved at reduced pressure and the crude was purified by elutionthrough basic alumina (Hexanes:EtOAc 1:1). 37 mg (10% yield) of compound383 were obtained as a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆) dppm 7.99 (d, 1H), 7.75 (dd, 1H), 7.38-7.62 (m, 5H), 6.91 (s, 1H), 6.62(dd, 1H), 3.94 (s, 3H)

Synthesis of Compound 384

Compound 384 was prepared as follows.

N-(3-(5-iodo-2-oxopyridin-1(2H)-yl)phenyl)acetamide (0.050 g, 0.14 mmol)was dissolved in dry and degassed toluene (3 mL). The catalyst was thenadded (0.008 g, 0.007 mmol) and the mixture was stirred for 10 minutes.2-(tributylstannyl)oxazole (0.050 g, 0.14 mmol) was added and thereaction was heated at 90° C. for 18 h under nitrogen atmosphere. Conc.NH₄OH was added. The solvent was removed at reduced pressure and thecrude was purified by preparative HPLC. 16 mg (38.7% yield) of compound384 were obtained as a pale yellow solid. ¹H NMR (300 MHz, DMSO-d6) ppm10.15 (br. s., 1H), 8.16-8.21 (m, 1H), 8.14 (d, 1H), 8.02 (dd, 1H), 7.76(t, 1H), 7.61 (ddd, 1H), 7.46 (dd, 1H), 7.32 (d, 1H), 7.16 (ddd, 1H),6.65 (dd, 1H), 2.07 (s, 3H)

Synthesis of Compound 385

Compound 385 was prepared as follows.

Following standard Suzuki coupling, the product was obtained by reactionof 2.82 g (15 mmol) of 5-bromo-2-methoxy-pyridine. After purification(SiO₂; Hexanes:EtOAc 9:1) 2.8 g (92% yield) of pure product wereobtained as white solid. The intermediate (900 mg) was dissolved in HBr48% (10 ml) and EtOH (3 ml) and the solution was heated at reflux for 3h. After evaporation of volatiles the desired pyridone was obtained aswhite solid (780 mg, 93% yield).

Following general procedure H1A, compound 385 was prepared in 35% yield.¹H NMR (300 MHz, DMSO-d6) ppm 7.86-7.99 (m, 1H), 7.82 (d, 1H), 7.58-7.73(m, 2H), 7.12-7.30 (m, 3H), 6.94 (d, 1H), 6.87 (dd, 1H), 6.58 (d, 1H),4.08 (q, 2H), 2.04 (s, 3H), 1.35 (t, 3H)

Synthesis of Compound 386

Compound 386 was prepared as follows.

Following standard procedure for Suzuki coupling, the intermediate wasobtained by reaction of 3 g (16 mmol) of 5-bromo-2-methoxy-pyridine.After purification (SiO₂; Hexanes:EtOAc 20:1 to 100% EtOAc) 2.2 g (51%yield) of pure product were obtained as white solid. To a magneticallystirred solution of 2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-pyridine (1.2g, 6.3 mmol), in 3 mL of EtOH, 15 mL of HBr were added. The mixture washeated at 80° C. for 20 h. The reaction was cooled at room temperature.The solvent was evaporated under vacuum. Purification by flash columnchromatography (SiO₂; 100% AcOEt) afforded 1.1 g of the intermediatecompound (quantitative yield).

Following general procedure H1A, compound 386 was prepared from thisintermediate in 22% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.01 (s, 1H),7.71-7.81 (m, 3H), 7.16 (d, 1H), 6.94 (d, 1H), 6.86 (dd, 1H), 6.52 (dd,1H), 4.08 (q, 2H), 3.81 (s, 3H), 2.02 (s, 3H), 1.35 (t, 3H)

Synthesis of Compound 387

Compound 387 was prepared as follows.

Following the standard procedure for Suzuki coupling, the intermediatewas obtained by reaction of 3.2 g (16 mmol) of5-bromo-2-methoxy-4-methylpyridine. After purification (SiO₂;Hexanes:EtOAc 20:1 to 100% EtOAc) 2 g (62% yield) of pure product wasobtained as white solid. A solution of2-methoxy-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)pyridine (2 g, 9.9 mmol)in EtOH (6 ml) and HBr 48% (12 ml) was stirred at 90° C. for 24 h. Thesolvent was evaporated and the crude compound (as hydrobromide salt) wasutilized in the next step without any purification. Quantitative yield.

Following general procedure H1A, compound 387 was prepared from thisintermediate in 33% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.88 (s, 1H),7.59 (d, 1H), 7.34-7.55 (m, 6H), 6.43 (s, 1H), 3.84 (s, 3H), 2.23 (d,3H)

Synthesis of Compound 388

Similar to compound 387, compound 388 was prepared in 41% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.10 (s, 1H), 7.87 (s, 1H), 7.69 (t, 1H),7.51-7.61 (m, 2H), 7.48 (s, 1H), 7.41 (dd, 1H), 7.08 (ddd, 1H), 6.42 (s,1H), 3.84 (s, 3H), 2.23 (d, 3H), 2.05 (s, 3H)

Synthesis of Compound 389

Compound 389 was prepared as follows.

Following standard procedure for Suzuki coupling, the intermediate wasobtained by reaction of 420 mg (3 mmol) of 5-bromo-2-methoxy-pyridine.After purification (SiO₂; Hexanes:EtOAc 95:5) 390 mg (65% yield) of pureproduct was obtained as white solid. The intermediate (390 mg) wasdissolved in HBr 48% (5 ml) and EtOH (5 ml) and the solution was heatedat reflux for 24 h. After evaporation of volatiles the desired pyridonewas obtained as white solid (359 mg, quantitative yield).

Following general procedure H1A, compound 389 was prepared from thisintermediate in 51% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.06 (d, 1H),7.97 (dd, 1H), 7.34-7.61 (m, 8H), 7.00-7.20 (m, 1H), 6.60 (d, 1H)

Synthesis of Compound 390

Similar to compound 389, compound 390 was prepared in 38% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 8.05 (d, 1H), 7.97 (dd, 1H),7.70-7.77 (m, 1H), 7.58-7.65 (m, 1H), 7.49-7.58 (m, 1H), 7.36-7.49 (m,3H), 7.02-7.20 (m, 2H), 6.60 (d, 1H), 2.06 (s, 3H)

Synthesis of Compound 391

Similar to compound 387, compound 391 was prepared in 26% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 7.86 (s, 1H), 7.57 (d, 1H), 7.35 (s, 1H), 7.12(d, 1H), 6.91 (d, 1H), 6.84 (dd, 1H), 6.40 (s, 1H), 4.06 (q, 2H), 3.83(s, 3H), 2.24 (d, 3H), 2.02 (s, 3H), 1.34 (t, 3H)

Synthesis of Compound 392

Compound 392 was prepared from the intermediate aryl group as follows.

Following the standard procedure for Suzuki coupling, the product wasobtained by reaction of 2.7 g (14.4 mmol) of 5-bromo-2-methoxy-pyridine.After purification (SiO₂; Hexanes:EtOAc 1:1 to 100% EtOAc) 1.29 g mg(48% yield) of pure product was obtained as white solid. A solution of5-(6-Methoxy-pyridin-3-yl)-pyrimidine (1.29 g, 6.9 mmol) in EtOH (4 ml)and HBr 48% (10 ml) was stirred at 90° C. for 7 h. The solvent wasevaporated and the crude compound (as hydrobromide salt) was utilized inthe next step without any purification.

Following general procedure H1A, compound 392 was prepared from thisintermediate in 21% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 9.07-9.12 (m,3H), 8.14 (dd, 1H), 8.06 (dd, 1H), 7.21 (d, 1H), 6.96 (d, 1H), 6.88 (dd,1H), 6.64 (dd, 1H), 4.08 (q, 2H), 2.06 (s, 3H), 1.35 (t, 3H)

Synthesis of Compound 393

Similar to synthesis of compound 380, compound 393 was prepared in 41%yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.66-8.83 (m, 2H), 7.85-7.97 (m,2H), 7.61-7.68 (m, 2H), 7.58 (m, 2H), 6.98 (m, 2H), 6.54-6.66 (m, 1H),3.78 (s, 3H)

Synthesis of Compound 394

Similar to synthesis of compound 380, compound 394 was prepared in 33%yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.82-7.92 (m, 2H), 7.43-7.61 (m,7H), 6.97 (m, 2H), 6.58 (dd, 1H), 3.77 (s, 3H)

Synthesis of Compound 395

Similar to synthesis of compound 380, compound 395 was prepared in 42%yield. ¹H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 7.88 (dd, 1H), 7.83(d, 1H), 7.70-7.76 (m, 1H), 7.58-7.64 (m, 1H), 7.54 (m, 2H), 7.44 (dd,1H), 7.14 (ddd, 1H), 6.97 (m, 2H), 6.57 (d, 1H), 3.77 (s, 3H), 2.06 (s,3H)

Synthesis of Compound 396

Similar to compound 387, compound 396 was prepared in 23% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 7.88 (s, 1H), 7.43-7.69 (m, 6H), 6.45 (s, 1H),3.84 (s, 3H), 2.24 (d, 3H)

Synthesis of Compound 397

Compound 397 was prepared from an intermediate heteroaryl prepared asfollows.

Following the standard procedure for Suzuki coupling, the intermediatewas obtained by reaction of 3 g (16 mmol) of 5-bromo-2-methoxy-pyridine.After purification (SiO₂; Hexanes:EtOAc 1:1 to 100% EtOAc) 750 mg (31%yield) of pure product was obtained as white solid.5-(2-fluorophenyl)-2-methoxypyridine (750 mg) was dissolved in HBr 48%(10 ml) and EtOH (3 ml) and the solution was heated at reflux for 3 h.After evaporation of volatiles the desired pyridone was obtained aswhite solid (700 mg, quantitative yield).

Following general procedure H1A, compound 397 was prepared from thisintermediate in 34% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.74-7.83 (m,1H), 7.67-7.73 (m, 1H), 7.51-7.61 (m, 1H), 7.17-7.42 (m, 4H), 6.94 (d,1H), 6.87 (dd, 1H), 6.59 (dd, 1H), 4.08 (q, 2H), 2.05 (s, 3H), 1.35 (t,3H)

Synthesis of Compound 398

Similar to compound 389, compound 398 was prepared in 30% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.13 (d, 1H), 7.99 (dd, 1H), 7.62-7.76 (m, 2H),7.34-7.62 (m, 5H), 7.02-7.20 (m, 1H), 6.62 (d, 1H)

Synthesis of Compound 399

Following general procedure A, compound 399 was prepared in 44% yield.¹H NMR (300 MHz, DMSO-d6) ppm 12.24 (br. s., 1H), 10.11 (s, 1H), 7.73(m, 1H), 7.57 (m, 1H), 7.51 (dd, 1H), 7.35-7.47 (m, 2H), 7.10 (ddd, 1H),6.54 (d, 1H), 2.17 (br. s., 6H), 2.06 (s, 3H)

Synthesis of Compound 400

Similar to synthesis of compound 380, compound 400 was prepared in 36%yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.89 (dd, 1H), 7.72 (d, 1H), 7.53(m, 2H), 7.19 (d, 1H), 6.91-7.04 (m, 3H), 6.86 (dd, 1H), 6.56 (d, 1H),4.08 (q, 2H), 3.77 (s, 3H), 2.04 (s, 3H), 1.35 (t, 3H)

Synthesis of Compound 401

Compound 401 was synthesized as follows.

6-methoxynicotinaldehyde (1.0 g, 7.2 mmol) was dissolved in HBr 48% (10mL) and EtOH (3 mL) and the solution was heated at reflux for 2 h. Afterevaporation of volatiles 1.6 g of the desired pyridone was obtained. Theproduct was used in the next step without further purification. To asolution of 6-oxo-1,6-dihydropyridine-3-carbaldehyde (300 mg, 2.4 mmol)in DMF (10 mL), Cu(OAc)₂ (0.88 g, 4.8 mmol), 3-acetamidophenyl boronicacid (0.5 g, 2.8 mmol), pyridine (0.42 mL, 2.8 mmol) and finelygrounded, activated 4 Å molecular sieves (1 g) were added. The mixturewas stirred at room temperature for 24 h. A concentrated solution ofNH₄OH was added. The solvents were evaporated under vacuum, and theresulting crude was purified by chromatographic column (SiO₂;Hexanes:EtOAc 9:1 to 100% EtOAc). 370 mg (38.5% yield) of pure productwere obtained as a white solid. To a solution ofN-(3-(5-formyl-2-oxopyridin-1(2H)-yl)phenyl)acetamide (370 mg, 0.94mmol) in MeOH (20 mL), glioxal (0.4 mL, 3.4 mmol) was added at 0° C.Gaseous NH₃ was bubbled into the mixture at 0° C. for 1 h. The reactionwas warmed at room temperature and stirred for 24 h. The solvent wasevaporated under vacuum and the resulting crude was purified by flashchromatography (SiO₂, Hexanes:EtOAc 9:1 to 100% EtOAc). 100 mg (24.6%yield) of compound 401 were obtained. ¹H NMR (300 MHz, DMSO-d6) ppm10.20 (s, 1H), 8.49 (d, 1H), 8.03 (dd, 1H), 7.83-7.91 (m, 1H), 7.67 (s,2H), 7.54-7.62 (m, 1H), 7.50 (dd, 1H), 7.15 (ddd, 1H), 6.75 (d, 1H),2.07 (s, 3H)

Synthesis of Compound 402

Following general procedure H1A, compound 402 was prepared in 17% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.16 (s, 1H), 8.24-8.34 (m, 1H), 8.19 (d,1H), 7.69-7.79 (m, 1H), 7.56-7.65 (m, 1H), 7.38-7.51 (m, 1H), 7.16 (ddd,1H), 2.06 (s, 3H)

Synthesis of Compound 403

Similar to compound 387, compound 403 was prepared in 34% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.71 (dd, 2H), 7.90 (s, 1H), 7.54-7.64 (m, 4H),6.47 (s, 1H), 3.85 (s, 3H), 2.24 (d, 3H)

Synthesis of Compound 405

Compound 405 was prepared from an intermediate heteroaryl synthesized asfollows.

A mixture of 2-methoxy-5-aminopyridine (10 g, 0.08 mol) in AcOH (125mL), and concentrated HCl (150 mL) was cooled at 0° C. in an ice/waterbath. A solution of NaNO₂ (4.0 g, 0.058 mol) in water (15 mL) was addeddropwise at 0° C. The resulting mixture was stirred for 45 minutes at 0°C. In the meantime, in a separate round bottom flask, 150 mL ofconcentrated HCl was added dropwise to a sodium bisulphite solution. Thegaseous SO₂ thus formed was purged for 2-3 h into a third round bottomflask containing AcOH cooled at −20° C. CuCl₂ (18 g) was added, and thereaction was stirred for 20 minutes at −20° C. The mixture was addeddropwise to the 2-methoxy-5-aminopyridine/AcOH/concentrated HCl mixturemaintained at 0° C. The reaction was allowed to warm up to roomtemperature and stirred overnight. The mixture was quenched with waterand the solid thus formed was filtered, re-dissolved in DCM and filteredthrough celite. The clear solution was dried over Na₂SO₄ andconcentrated under vacuum to afford 10.2 g (61% yield) of pure6-methoxy-pyridine-3-sulfonyl chloride. 6-Methoxy-pyridine-3-sulfonylchloride (5.0 g, 0.025 mol) was dissolved in DCM and cooled at 0° C.Gaseous NH₃ was bubbled in the solution for 10 min. The resulting palebrown suspension was filtered and the solid was triturated with water.The resulting white solid was filtered and dried under vacuum to afford3.2 g (70.6% yield) of pure 6-Methoxy-pyridine-3-sulfonamide.6-Methoxy-pyridine-3-sulfonamide (0.752 g, 4.0 mmol) was dissolved inEtOH (6 mL). An excess of 48% HBr aqueous solution (12 mL) was added andthe reaction was heated at 90° C. for 20 h. The solvent was removedunder reduced pressure and the residual hydrobromic acid was furtherdried under reduced pressure, at 40° C. Quantitative yield.

Following general procedure H1A, compound 405 was prepared from thisintermediate in 28% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.86 (d, 1H),7.79 (dd, 1H), 7.35 (s, 2H), 7.19 (d, 1H), 6.96 (d, 1H), 6.88 (dd, 1H),6.64 (d, 1H), 4.08 (q, 2H), 2.02 (s, 3H), 1.35 (t, 3H)

Synthesis of Compound 406

Following general procedure H1A, compound 406 was prepared in 38% yield.¹H NMR (300 MHz, DMSO-d6) ppm 8.29 (dd, 1H), 8.20 (d, 1H), 7.42-7.65 (m,5H)

Synthesis of Compound 407

Compound 407 was prepared as follows:

Following the standard procedure for Suzuki coupling, the product wasobtained by reaction of 1.02 g (5.4 mmol) of 5-bromo-2-methoxy-pyridine.After purification (SiO₂; Hexanes:EtOAc 20:1 to 100% EtOAc) 1.12 g (96%yield) of pure product were obtained as white solid. A solution of2-Methoxy-5-(4-methoxy-phenyl)-pyridine (1.12 g, 5.2 mmol) in EtOH (5ml) and HBr 48% (10 ml) was stirred at 80° C. for 48 h. The solvent wasevaporated and the crude compound (as hydrobromide salt) was utilized inthe next step without any purification (quantitative yield).

Compound 407 was prepared from this intermediate using general procedureH1A in 35% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.98 (dd, 1H), 7.93 (dd,1H), 7.39-7.62 (m, 5H), 7.32 (dd, 1H), 7.13-7.23 (m, 2H), 6.81-6.92 (m,1H), 6.59 (dd, 1H), 3.80 (s, 3H)

Synthesis of Compound 408

Similar to compound 407, compound 408 was prepared in 38% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.05 (d, 1H), 7.95 (dd, 1H), 7.67 (m, 2H), 7.54(m, 2H), 7.32 (dd, 1H), 7.15-7.24 (m, 2H), 6.83-6.93 (m, 1H), 6.61 (d,1H), 3.80 (s, 3H)

Synthesis of Compound 409

Compound 409 was prepared as follows.

Following standard procedure for Suzuki coupling the intermediate wasobtained by reaction of 3 g (16 mmol) of 5-bromo-2-methoxy-pyridine.After purification (SiO₂; Hexanes:EtOAc 9:1) 3.1 g (70% yield) of pureproduct were obtained as white solid. The intermediate (3.1 g) wasdissolved in HBr 48% (10 ml) and EtOH (5 ml) and the solution was heatedat reflux for 24 h. After evaporation of volatiles the desired pyridonewas obtained as white solid (2.9 g, quantitative yield).

Compound 409 was prepared following general procedure H1A in 36% yield.¹H NMR (300 MHz, DMSO-d6) ppm 7.73 (dd, 1H), 7.69 (dd, 1H), 7.41-7.57(m, 5H), 7.37 (dd, 1H), 7.32 (ddd, 1H), 7.09 (dd, 1H), 6.99 (ddd, 1H),6.53 (dd, 1H), 3.80 (s, 3H)

Synthesis of Compound 410

Similar to the preparation of compound 409, compound 410 was prepared in13% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.70-7.79 (m, 2H), 7.66 (m,2H), 7.52 (m, 2H), 7.38 (dd, 1H), 7.33 (ddd, 1H), 7.10 (dd, 1H), 6.99(td, 1H), 6.55 (d, 1H), 3.80 (s, 3H)

Synthesis of Compound 411

Following general procedure A, compound 411 was prepared in 51% yield.¹H NMR (300 MHz, DMSO-d6) ppm 12.24 (br. s., 1H), 7.37-7.59 (m, 7H),6.54 (dd, 1H), 2.17 (br. s., 6H)

Synthesis of Compound 412

Similar to the preparation of compound 409, compound 412 was prepared in26% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.74 (dd, 1H), 7.55 (d, 1H),7.25-7.38 (m, 2H), 7.18 (d, 1H), 7.08 (dd, 1H), 6.98 (ddd, 1H), 6.94 (d,1H), 6.85 (dd, 1H), 6.52 (d, 1H), 4.07 (q, 2H), 3.79 (s, 3H), 2.06 (s,3H), 1.35 (t, 3H)

Synthesis of Compound 413

Compound 413 was prepared as follows.

To a suspension of A (2.9 mmol) in a MeOH:Water (10 mL:1 mL) mixture, asolution of NaOH in water (2.9 mmol in 2 mL of Water) was added at −30°C. To the stirred reaction, a solution of 2-aminoacetamide (2.9 mmol) inMeOH (2 mL) was added. The mixture was stirred at the same temperaturefor 1 h, then warmed at room temperature and stirred for additional 3 h.AcOH was added until pH 5 and the volatile portion was evaporated undervacuum. The remaining mixture was portioned between Water (10 mL) andEthyl Acetate (10 mL). The organic layer was dried over Na₂SO₄, filteredand evaporated under vacuum.

Following general procedure H1A, compound 413 was prepared from thisintermediate in 51% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.26 (d, 1H),8.21 (d, 1H), 7.87-8.00 (m, 2H), 7.48-7.62 (m, 5H), 7.38-7.47 (m, 2H),7.28-7.36 (m, 1H)

Synthesis of Compound 415

Similar to compound 407, compound 415 was prepared in 23% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 7.86-8.01 (m, 2H), 7.73 (t, 1H),7.53-7.68 (m, 1H), 7.44 (dd, 1H), 7.32 (dd, 1H), 7.10-7.23 (m, 3H),6.80-6.93 (m, 1H), 6.59 (dd, 1H), 3.79 (s, 3H), 2.06 (s, 3H)

Synthesis of Compound 416

Compound 416 was prepared as follows.

Following the standard procedure for Suzuki coupling, the product wasobtained by reaction of 1.02 g (5.4 mmol) of 5-bromo-2-methoxy-pyridine.After purification (SiO₂; Hexanes:EtOAc 20:1 to 100% EtOAc)) 1.06 g (89%yield) of pure product were obtained as white solid. A solution of2-Methoxy-5-(4-methoxy-phenyl)-pyridine (1.12 g, 5.2 mmol) in EtOH (5ml) and HBr 48% (10 ml) was stirred at 80° C. overnight. The solvent wasevaporated and the crude compound (as hydrobromide salt) was utilized inthe next step without any purification (quantitative yield).

Compound 416 was prepared from this intermediate following generalprocedure H1A in 41% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.00 (d, 1H),7.93 (dd, 1H), 7.68 (m, 2H), 7.36-7.59 (m, 7H), 6.60 (d, 1H)

Synthesis of Compound 417

Similar to compound 416, compound 417 was prepared in 44% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 7.99 (d, 1H), 7.93 (dd, 1H),7.71-7.78 (m, 1H), 7.67 (m, 2H), 7.54-7.63 (m, 1H), 7.39-7.49 (m, 3H),7.07-7.19 (m, 1H), 6.60 (d, 1H), 2.06 (s, 3H)

Synthesis of Compound 418

Similar to compound 407, compound 418 was prepared in 16% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 7.95 (dd, 1H), 7.86 (d, 1H), 7.30 (dd, 1H),7.11-7.24 (m, 3H), 6.95 (d, 1H), 6.80-6.91 (m, 2H), 6.57 (d, 1H), 4.08(q, 2H), 3.79 (s, 3H), 2.04 (s, 3H), 1.35 (t, 3H)

Synthesis of Compound 419

Following general procedure H1A, compound 419 was prepared in 28% yield.¹H NMR (300 MHz, DMSO-d6) ppm 8.33-8.44 (m, 1H), 8.21 (d, 1H), 7.68 (m,2H), 7.56 (m, 2H)

Synthesis of Compound 420

Similar to compound 416, compound 420 was prepared in 33.8% yield. ¹HNMR (300 MHz, DMSO-d6) ppm 7.94 (dd, 1H), 7.89 (d, 1H), 7.65 (m, 2H),7.44 (m, 2H), 7.20 (d, 1H), 6.94 (d, 1H), 6.87 (dd, 1H), 6.59 (d, 1H),4.08 (q, 2H), 2.04 (s, 3H), 1.35 (t, 3H)

Synthesis of Compound 421

Similar to compound 416, compound 421 was prepared in 31.5% yield. ¹HNMR (300 MHz, DMSO-d6) ppm 8.07 (d, 1H), 7.95 (dd, 1H), 7.63-7.73 (m,4H), 7.53 (m, 2H), 7.46 (m, 2H), 6.62 (d, 1H)

Synthesis of Compound 422

Similar to compound 413, compound 422 was prepared in 35% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.25 (d, 1H), 8.23 (d, 1H), 7.91-8.03 (m, 2H),7.44-7.65 (m, 5H), 7.17-7.33 (m, 2H)

Synthesis of Compound 423

Similar to compound 407, compound 423 was prepared in 34% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.63-8.87 (m, 2H), 8.04 (d, 1H), 7.97 (dd, 1H),7.58-7.69 (m, 2H), 7.33 (t, 1H), 7.15-7.27 (m, 2H), 6.81-6.94 (m, 1H),6.63 (d, 1H), 3.80 (s, 3H)

Synthesis of Compound 424

Compound 424 was prepared as follows.

In a round bottom flask, glyoxylic acid B (22 mmol) and 4-F acetophenoneA (8 mmol) were mixed together and the reaction was heated at 115° C.overnight, then allowed to cool down at room temperature. Water (5 mL)and concentrated NH₄OH (1 mL), were poured into the reaction vessel andthe mixture was extracted with DCM (3×5 mL). To the aqueous basicsolution hydrazine (8 mmol) was added and the reaction was stirred at100° C. for 2 h. The precipitate thus formed was collected by filtrationand washed with plenty of water. The desired compound was recovered as alight yellow solid (45% yield). ¹H NMR (300 MHz, DMSO-d6) ppm 13.15 (br.s., 1H) 8.01 (d, 1H) 7.91 (m, 2H) 7.31 (m, 2H) 6.97 (d, 1H)

Following general procedure H1A, compound 424 was prepared from thisintermediate in 74% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H),8.14 (d, 1H), 7.94-8.01 (m, 2H), 7.90-7.94 (m, 1H), 7.57-7.66 (m, 1H),7.43 (t, 1H), 7.28-7.39 (m, 3H), 7.18 (d, 1H), 2.06 (s, 3H)

Synthesis of Compound 425

Compound 425 was prepared as follows.

Following standard procedure for Suzuki coupling, the intermediate wasobtained by reaction of 3 g (16 mmol) of 5-bromo-2-methoxy-pyridine.After purification (SiO₂; Hexanes:EtOAc 1:1 to 100% EtOAc) 3.99 g (95%yield) of pure product was obtained as white solid. The intermediate(3.99 g) was dissolved in HBr 48% (12 ml) and EtOH (6 ml) and thesolution was heated at reflux for 24 h. After evaporation of volatilesthe desired pyridone was obtained as white solid (3.72 g, quantitativeyield).

Compound 425 was prepared following general procedure H1A with thisintermediate in 42% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 7.74 (d, 1H),7.67 (dd, 1H), 7.32-7.60 (m, 9H), 6.57 (d, 1H)

Synthesis of Compound 426

Following general procedure H1A, compound 426 was prepared in 8% yield.¹H NMR (300 MHz, DMSO-d6) ppm 9.30 (s, 1H), 9.04 (s, 2H), 8.47-8.64 (m,1H), 8.28 (d, 1H)

Synthesis of Compound 427

Similar to the preparation of compound 409, compound 427 was prepared in45% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.67-8.79 (m, 2H), 7.68-7.82(m, 2H), 7.59-7.68 (m, 2H), 7.39 (dd, 1H), 7.34 (ddd, 1H), 7.10 (dd,1H), 7.00 (td, 1H), 6.54-6.61 (m, 1H), 3.80 (s, 3H)

Synthesis of Compound 428

Similar to compound 424, compound 428 was prepared in 94% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 8.14 (d, 1H), 7.90-8.04 (m, 2H), 7.61-7.71 (m,2H), 7.49-7.59 (m, 2H), 7.40-7.49 (m, 1H), 7.26-7.40 (m, 2H), 7.19 (d,1H)

Synthesis of Compound 429

Following general procedure A, compound 429 was prepared in 26% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.14 (s, 1H), 8.19 (t, 1H), 8.17 (d, 1H),7.94-8.08 (m, 2H), 7.69-7.81 (m, 2H), 7.52-7.66 (m, 2H), 7.45 (dd, 1H),7.10-7.21 (m, 1H), 6.62 (d, 1H), 2.07 (s, 3H)

Synthesis of Compound 430

Following general procedure A, compound 430 was prepared in 44% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 8.17 (d, 1H), 7.98-8.06 (m,1H), 7.81-7.91 (m, 4H), 7.71-7.78 (m, 1H), 7.56-7.66 (m, 1H), 7.45 (t,1H), 7.15 (ddd, 1H), 6.63 (d, 1H), 2.06 (s, 3H)

Synthesis of Compound 431

Similar to compound 416, compound 431 was prepared in 20.3% yield. ¹HNMR (300 MHz, DMSO-d6) ppm 9.25 (s, 1H), 9.07 (s, 2H), 8.22 (d, 1H),8.00 (dd, 1H), 7.69 (m, 2H), 7.48 (m, 2H), 6.66 (d, 1H)

Synthesis of Compound 432

Similar to preparation of compound 433, compound 432 was prepared in6.7% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 9.26 (s, 1H), 9.08 (s, 2H),8.29 (d, 1H), 8.04 (dd, 1H), 7.79 (t, 1H), 7.60-7.69 (m, 1H), 7.46 (dd,1H), 7.33-7.42 (m, 1H), 6.67 (d, 1H)

Synthesis of Compound 433

Compound 433 was prepared as follows.

Following standard procedure for Suzuki coupling, the product wasobtained by reaction of 1.02 g (5.4 mmol) of 5-bromo-2-methoxy-pyridine.After purification (SiO₂; Hexanes:EtOAc 20:1 to 100% EtOAc) 1.06 g (80%yield) of pure product were obtained as white solid. A solution of2-Methoxy-5-(4-methoxy-phenyl)-pyridine (949 mg, 4.3 mmol) in EtOH (10ml) and HBr 48% (10 ml) was stirred at 80° C. overnight. The solvent wasevaporated and the crude compound (as hydrobromide salt) was utilized inthe next step without any purification (quantitative yield).

Compound 433 was prepared following general procedure H1A from thisintermediate in 13% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.14 (d, 1H),7.98 (dd, 1H), 7.78 (t, 1H), 7.67 (m, 2H), 7.62 (ddd, 1H), 7.54 (m, 2H),7.43 (dd, 1H), 7.35 (ddd, 1H), 6.62 (d, 1H)

Synthesis of Compound 434

Similar to the preparation of compound 425, compound 434 was prepared in30% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 10.12 (br. s., 1H), 7.74-7.78(m, 1H), 7.70-7.74 (m, 1H), 7.67 (dd, 1H), 7.47-7.62 (m, 3H), 7.35-7.47(m, 3H), 7.14 (ddd, 1H), 6.57 (dd, 1H), 2.06 (s, 3H)

Synthesis of Compound 435

Similar to the preparation of compound 409, compound 435 was prepared in20% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 7.77 (t, 1H),7.72 (dd, 1H), 7.69 (dd, 1H), 7.52-7.61 (m, 1H), 7.43 (dd, 1H),7.28-7.39 (m, 2H), 7.14 (ddd, 1H), 7.09 (dd, 1H), 6.99 (ddd, 1H), 6.53(dd, 1H), 3.80 (s, 3H), 2.06 (s, 3H)

Synthesis of Compound 436

Similar to the preparation of compound 409, compound 436 was prepared in23% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 9.24 (s, 1H), 9.06 (s, 2H),7.89 (dd, 1H), 7.79 (dd, 1H), 7.40 (dd, 1H), 7.35 (ddd, 1H), 7.11 (dd,1H), 7.01 (td, 1H), 6.59 (dd, 1H), 3.81 (s, 3H)

Synthesis of Compound 437

Similar to the preparation of compound 425, compound 437 was prepared in20% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.65-8.82 (m, 2H), 7.83 (d,1H), 7.71 (dd, 1H), 7.61-7.66 (m, 2H), 7.50-7.61 (m, 2H), 7.36-7.45 (m,2H), 6.62 (d, 1H)

Synthesis of Compound 438

Compound 438 was prepared as follows.

5-bromo-2-methoxy-4-methylpyridine (1.0 g, 4.95 mmol) was dissolved inHBr 48% (10 mL) and EtOH (10 mL) and the solution was heated at 90° C.for 24 h. After evaporation of volatiles, 930 mg (quantitative yield) ofthe desired pyridone were obtained as a white solid.5-bromo-4-methyl-1-phenylpyridin-2(1H)-one was obtained by reaction of450 mg (2.39 mmol) of 5-bromo-4-methylpyridin-2(1H)-one withphenylboronic acid. After purification (SiO₂; Hexanes:EtOAc 9:1 to 1:1)250 mg (39.7% yield) of compound 438 were obtained as a white solid. ¹HNMR (300 MHz, DMSO-d6) ppm 7.93 (s, 1H), 7.32-7.58 (m, 5H), 6.47-6.57(m, 1H), 2.24 (d, 3H)

Synthesis of Compound 439

Similar to compound 385, compound 439 was prepared in 51% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 7.84-7.98 (m, 2H), 7.58-7.74 (m, 2H), 7.43 (t,1H), 7.16-7.30 (m, 2H), 6.97-7.13 (m, 3H), 6.59 (dd, 1H), 3.81 (s, 3H)

Synthesis of Compound 440

Similar to compound 385, compound 440 was prepared in 47% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 7.98 (dd, 1H), 7.92 (dd, 1H), 7.64-7.74 (m, 2H),7.57 (ddd, 1H), 7.29-7.41 (m, 2H), 7.15-7.29 (m, 2H), 6.61 (dd, 1H)

Synthesis of Compound 441

Similar to compound 385, compound 441 was prepared in 55% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 7.95 (dd, 1H), 7.91 (dd, 1H), 7.62-7.72 (m, 2H),7.50-7.62 (m, 2H), 7.29-7.42 (m, 2H), 7.16-7.29 (m, 2H), 6.59 (dd, 1H)

Synthesis of Compound 442

Following general procedure A, compound 442 was prepared in 68% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 8.02 (d, 1H), 7.94-8.01 (m,1H), 7.78 (dd, 1H), 7.71 (t, 1H), 7.56-7.65 (m, 2H), 7.52 (dd, 1H), 7.45(t, 1H), 7.12 (ddd, 1H), 6.57 (d, 1H), 2.06 (s, 3H)

Synthesis of Compound 443

Following general procedure A, compound 443 was prepared in 55% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.14 (s, 1H), 8.16 (d, 1H), 8.03 (dd,1H), 7.93 (s, 4H), 7.76 (s, 1H), 7.61 (dt, 1H), 7.46 (t, 1H), 7.16 (ddd,1H), 6.64 (d, 1H), 3.23 (s, 3H), 2.07 (s, 3H)

Synthesis of Compound 444

Following general procedure A, compound 444 was prepared in 70% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.14 (s, 1H), 8.18 (d, 1H), 8.14 (t, 1H),8.03 (dd, 1H), 7.94-8.01 (m, 1H), 7.79-7.88 (m, 1H), 7.75 (s, 1H), 7.68(t, 1H), 7.60-7.65 (m, 1H), 7.46 (t, 1H), 7.09-7.23 (m, 1H), 6.64 (d,1H), 3.25 (s, 3H), 2.07 (s, 3H)

Synthesis of Compound 445

Similar to compound 385, compound 445 was prepared in 54% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 11.29 (s, 1H), 10.06 (s, 1H), 8.44 (s, 1H),8.03-8.11 (m, 1H), 7.85 (d, 1H), 7.65-7.76 (m, 1H), 7.62 (s, 1H),7.36-7.48 (m, 2H), 7.22-7.35 (m, 3H), 7.02-7.14 (m, 2H), 6.23 (d, 1H),4.71 (spt, 1H), 1.35 (d, 6H)

Synthesis of Compound 446

Following general procedure A, compound 446 was prepared in 78% yield.¹H NMR (300 MHz, DMSO-d6) ppm 8.19-8.21 (m, 1H), 8.17 (d, 1H), 7.93-8.07(m, 2H), 7.74 (ddd, 1H), 7.60 (dd, 1H), 7.43-7.58 (m, 5H), 6.62 (d, 1H)

Synthesis of Compound 447

Similar to compound 385, compound 447 was prepared in 25% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 7.82-7.94 (m, 2H), 7.57-7.74 (m, 2H), 7.41 (m,2H), 7.16-7.30 (m, 2H), 7.06 (m, 2H), 6.48-6.65 (m, 1H), 3.82 (s, 3H)

Synthesis of Compound 448

Similar to compound 385, compound 448 was prepared in 33% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 7.89 (dd, 1H), 7.83 (d, 1H), 7.57-7.69 (m, 2H),7.39-7.51 (m, 1H), 7.35 (dd, 1H), 7.14-7.28 (m, 3H), 7.08 (td, 1H), 6.56(d, 1H), 3.77 (s, 3H)

Synthesis of Compound 449

Similar to compound 385, compound 449 was prepared in 38% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 7.99 (d, 1H), 7.92 (dd, 1H), 7.63-7.74 (m, 3H),7.44-7.61 (m, 3H), 7.16-7.30 (m, 2H), 6.60 (dd, 1H)

Synthesis of Compound 450

Following general procedure A, compound 450 was prepared in 82% yield.¹H NMR (300 MHz, DMSO-d6) ppm 8.17-8.21 (m, 1H), 8.15 (t, 1H), 7.97-8.07(m, 2H), 7.83 (ddd, 1H), 7.68 (dd, 1H), 7.41-7.62 (m, 5H), 6.64 (d, 1H),3.25 (s, 3H)

Synthesis of Compound 451

Following general procedure A, compound 451 was prepared in 70% yield.¹H NMR (300 MHz, DMSO-d6) ppm 8.04 (d, 1H), 7.97 (dd, 1H), 7.78 (dd,1H), 7.40-7.63 (m, 7H), 6.57 (dd, 1H)

Synthesis of Compound 452

Following general procedure A, compound 452 was prepared in 65% yield.¹H NMR (300 MHz, DMSO-d6) ppm 9.40 (s, 1H), 7.43-7.64 (m, 8H), 7.40 (dd,1H), 7.32 (td, 1H), 7.24 (td, 1H), 6.57 (dd, 1H), 1.97 (s, 3H)

Synthesis of Compound 453

Similar to preparation of compound 433, compound 453 was prepared in 52%yield. ¹H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 8.07 (d, 1H), 7.96(dd, 1H), 7.69-7.78 (m, 2H), 7.56-7.67 (m, 2H), 7.45 (dd, 1H), 7.43 (dd,1H), 7.35 (ddd, 1H), 7.15 (ddd, 1H), 6.59 (d, 1H), 2.06 (s, 3H)

Synthesis of Compound 454

Following general procedure A, compound 454 was prepared in 60% yield.¹H NMR (300 MHz, DMSO-d6) ppm 9.95 (s, 1H), 7.84-7.95 (m, 2H), 7.39-7.66(m, 9H), 6.53-6.64 (m, 1H), 2.04 (s, 3H)

Synthesis of Compound 455

Following general procedure A, compound 455 was prepared in 74% yield.¹H NMR (300 MHz, DMSO-d6) ppm 8.43 (dd, 1H), 7.98 (dd, 1H), 7.96 (d,1H), 7.87-7.94 (m, 1H), 7.36-7.59 (m, 5H), 6.85 (dd, 1H), 6.60 (dd, 1H),3.87 (s, 3H)

Synthesis of Compound 456

Following general procedure A, compound 456 was prepared in 82% yield.¹H NMR (300 MHz, DMSO-d6) ppm 7.83 (d, 1H), 7.73 (dt, 1H), 7.64 (td,1H), 7.42-7.58 (m, 5H), 7.34 (ddd, 1H), 7.15 (dddd, 1H), 6.60 (d, 1H)

Synthesis of Compound 457

Following general procedure A, compound 457 was prepared in 82% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.11 (s, 1H), 7.81-7.92 (m, 2H), 7.73 (t,1H), 7.60 (ddd, 1H), 7.44 (dd, 1H), 7.24 (d, 1H), 7.14 (ddd, 1H), 7.08(dd, 1H), 6.94 (d, 1H), 6.51-6.60 (m, 1H), 6.03 (s, 2H), 2.06 (s, 3H)

Synthesis of Compound 458

Following general procedure A, compound 458 was prepared in 89% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 9.93 (s, 1H), 7.81-7.87 (m,1H), 7.78-7.81 (m, 1H), 7.75 (br. s., 2H), 7.57-7.65 (m, 1H), 7.49-7.55(m, 1H), 7.45 (dd, 1H), 7.33 (dd, 1H), 7.28 (dt, 1H), 7.14 (ddd, 1H),6.62 (dd, 1H), 2.06 (s, 3H), 2.04 (s, 3H)

Synthesis of Compound 459

Following general procedure A, compound 459 was prepared in 56% yield.¹H NMR (300 MHz, DMSO-d6) ppm 9.68 (s, 1H), 7.74-7.85 (m, 2H), 7.40-7.58(m, 5H), 7.33 (dd, 1H), 7.07-7.18 (m, 1H), 6.92 (dt, 1H), 6.85 (tt, 1H),6.54 (dd, 1H)

Synthesis of Compound 460

Following general procedure A, compound 460 was prepared in 63% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.13 (br. s., 1H), 9.42 (br. s., 1H),7.79-7.85 (m, 1H), 7.46-7.58 (m, 4H), 7.44 (dd, 1H), 7.38 (dd, 1H), 7.32(td, 1H), 7.23 (td, 1H), 7.10 (ddd, 1H), 6.56 (d, 1H), 2.06 (s, 3H),1.97 (s, 3H)

Synthesis of Compound 461

Similar to compound 385, compound 461 was prepared in 52% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 10.10 (s, 1H), 7.82-7.96 (m, 2H), 7.58-7.75 (m,4H), 7.35-7.46 (m, 2H), 7.16-7.30 (m, 2H), 6.58 (dd, 1H), 2.08 (s, 3H)

Synthesis of Compound 462

Following general procedure A, compound 462 was prepared in 45% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 8.06-8.14 (m, 1H), 7.92 (d,1H), 7.84 (dd, 1H), 7.65-7.73 (m, 2H), 7.57-7.65 (m, 1H), 7.44 (dd, 1H),7.10 (ddd, 1H), 6.94 (dd, 1H), 6.56 (dd, 1H), 2.06 (s, 3H)

Synthesis of Compound 463

Following general procedure A, compound 463 was prepared in 28% yield.¹H NMR (300 MHz, DMSO-d6) ppm 8.17 (d, 1H), 8.02 (dd, 1H), 7.93 (s, 4H),7.41-7.61 (m, 5H), 6.64 (d, 1H), 3.23 (s, 3H)

Synthesis of Compound 464

Following general procedure A, compound 464 was prepared in 82% yield.¹H NMR (300 MHz, DMSO-d6) ppm 7.84 (dd, 1H), 7.70 (dd, 1H), 7.44-7.57(m, 5H), 7.43 (d, 1H), 6.60 (dd, 1H), 6.40 (d, 1H), 3.85 (s, 3H)

Synthesis of Compound 465

Following general procedure A, compound 465 was prepared in 81% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 7.84 (d, 1H), 7.79 (dd,1H), 7.71 (dd, 1H), 7.56-7.63 (m, 1H), 7.44 (dd, 1H), 7.21 (d, 1H), 7.11(ddd, 1H), 6.97-7.06 (m, 1H), 6.56 (d, 1H), 2.19 (s, 3H), 2.06 (s, 3H)

Synthesis of Compound 466

Following general procedure A, compound 466 was prepared in 74% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 9.44 (s, 1H), 7.78-7.92 (m,2H), 7.74 (t, 1H), 7.60 (d, 1H), 7.44 (dd, 1H), 7.20 (dd, 1H), 7.14(ddd, 1H), 7.01 (d, 1H), 6.95 (dd, 1H), 6.66-6.77 (m, 1H), 6.53-6.63 (m,1H), 2.06 (s, 3H)

Synthesis of Compound 467

Following general procedure A, compound 467 was prepared in 76% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 8.42 (d, 1H), 7.85-8.04 (m,3H), 7.74 (t, 1H), 7.56-7.66 (m, 1H), 7.44 (dd, 1H), 7.14 (ddd, 1H),6.85 (dd, 1H), 6.60 (dd, 1H), 3.87 (s, 3H), 2.06 (s, 3H)

Synthesis of Compound 468

Following general procedure A, compound 468 was prepared in 57% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.15 (s, 1H), 8.04-8.11 (m, 2H),7.92-8.04 (m, 2H), 7.69-7.85 (m, 3H), 7.56-7.67 (m, 1H), 7.42-7.55 (m,2H), 7.37 (br. s., 1H), 7.11-7.20 (m, 1H), 6.63 (d, 1H), 2.07 (s, 3H)

Synthesis of Compound 469

Following general procedure A, compound 469 was prepared in 68% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 8.06 (d, 1H), 7.98-8.03 (m,1H), 7.94-7.98 (m, 1H), 7.86-7.94 (m, 2H), 7.66-7.78 (m, 3H), 7.57-7.65(m, 1H), 7.45 (dd, 1H), 7.31 (br. s., 1H), 7.11-7.20 (m, 1H), 6.62 (d,1H), 2.07 (s, 3H)

Synthesis of Compound 470

Following general procedure A, compound 470 was prepared in 74% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 7.96 (dd, 1H), 7.83 (d,1H), 7.71-7.80 (m, 2H), 7.56-7.66 (m, 1H), 7.35-7.50 (m, 3H), 7.33 (d,1H), 7.17 (ddd, 1H), 6.59 (dd, 1H), 6.42 (dd, 1H), 3.80 (s, 3H), 2.07(s, 3H)

Synthesis of Compound 471

Following general procedure A, compound 471 was prepared in 85% yield.¹H NMR (300 MHz, DMSO-d6) ppm 7.95 (dd, 1H), 7.84 (d, 1H), 7.78 (d, 1H),7.43-7.59 (m, 6H), 7.40 (dd, 1H), 7.33 (d, 1H), 6.60 (d, 1H), 6.42 (dd,1H), 3.80 (s, 3H)

Synthesis of Compound 473

Following general procedure A, compound 473 was prepared in 66% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.13 (s, 1H), 7.69-7.78 (m, 1H),7.55-7.68 (m, 3H), 7.42 (d, 1H), 7.43 (dd, 1H), 7.13 (ddd, 1H), 6.97 (d,1H), 6.58 (d, 1H), 2.24 (s, 3H), 2.06 (s, 3H)

Synthesis of Compound 474

Similar to compound 385, compound 474 was prepared in 9% yield. ¹H NMR(300 MHz, DMSO-d6) ppm 9.36 (br. s., 1H), 7.90 (dd, 1H), 7.72 (d, 1H),7.54-7.70 (m, 3H), 7.29-7.50 (m, 3H), 7.13-7.29 (m, 2H), 6.57 (d, 1H),1.89 (s, 3H)

Synthesis of Compound 475

Following general procedure A, compound 475 was prepared in 94% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 7.88 (dd, 1H), 7.82 (d,1H), 7.71-7.75 (m, 1H), 7.60 (d, 1H), 7.53 (m, 2H), 7.44 (dd, 1H),7.09-7.18 (m, 1H), 6.95 (m, 2H), 6.57 (d, 1H), 4.04 (q, 2H), 2.06 (s,3H), 1.33 (t, 3H)

Synthesis of Compound 476

Following general procedure A, compound 476 was prepared in 51% yield.¹H NMR (300 MHz, DMSO-d6) ppm 9.93 (s, 1H), 7.80-7.88 (m, 2H), 7.75 (t,1H), 7.43-7.59 (m, 6H), 7.23-7.39 (m, 2H), 6.58-6.66 (m, 1H), 2.04 (s,3H)

Synthesis of Compound 477

Following general procedure A, compound 477 was prepared in 41% yield.¹H NMR (300 MHz, DMSO-d6) ppm 9.44 (br. s., 1H), 7.85 (dd, 1H), 7.83 (s,1H), 7.36-7.64 (m, 5H), 7.20 (t, 1H), 7.03 (ddd, 1H), 6.96 (dd, 1H),6.72 (ddd, 1H), 6.51-6.64 (m, 1H)

Synthesis of Compound 478

Following general procedure A, compound 478 was prepared in 54% yield.¹H NMR (300 MHz, DMSO-d6) ppm 7.59-7.69 (m, 2H), 7.43-7.57 (m, 5H), 7.42(d, 1H), 6.97 (d, 1H), 6.58 (dd, 1H), 2.25 (s, 3H)

Synthesis of Compound 479

Following general procedure A, compound 479 was prepared in 64% yield.¹H NMR (300 MHz, DMSO-d6) ppm 7.86 (d, 1H), 7.79 (dd, 1H), 7.36-7.60 (m,5H), 7.22 (d, 1H), 7.03 (t, 1H), 6.57 (d, 1H), 2.19 (d, 3H)

Synthesis of Compound 480

Following general procedure A, compound 480 was prepared in 25% yield.¹H NMR (300 MHz, DMSO-d6) ppm 9.45 (br. s., 1H), 7.84 (dd, 1H), 7.77(dd, 1H), 7.44-7.57 (m, 5H), 7.42 (m, 2H), 6.79 (m, 2H), 6.56 (dd, 1H)

Synthesis of Compound 481

Following general procedure A, compound 481 was prepared in 64% yield.¹H NMR (300 MHz, DMSO-d6) ppm 7.78-7.94 (m, 2H), 7.37-7.61 (m, 5H), 7.26(d, 1H), 7.09 (dd, 1H), 6.94 (d, 1H), 6.56 (d, 1H), 6.03 (s, 2H)

Synthesis of Compound 482

Compound 482 was prepared as follows.

Following standard procedure for Suzuki coupling, the product wasobtained by reaction of 264 mg (1.0 mmol) of3-bromo-N,N-dimethylbenzenesulfonamide. After purification (SiO₂;Hexanes:EtOAc 1:1) 293 mg (quantitative yield) of pure product wereobtained as white solid. A solution of3-(6-methoxypyridin-3-yl)-N,N-dimethylbenzenesulfonamide (292 mg, 1.0mmol) in EtOH (4 ml) and HBr 48% (4 ml) was stirred at 80° C. overnight.The solvent was evaporated and the crude compound (as hydrobromide salt)was purified by flash chromatography (DCM:MeOH 9:1). 278 mg wereobtained as a pale yellow solid (quantitative yield).

Following general procedure H1A, compound 482 was prepared from thisintermediate in 69% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.13 (d, 1H),7.94-8.04 (m, 2H), 7.92 (s, 1H), 7.63-7.74 (m, 2H), 7.37-7.61 (m, 5H),6.63 (d, 1H), 2.64 (s, 6H)

Synthesis of Compound 483

Compound 483 was prepared as follows.

Following the standard procedure for Suzuki coupling, the product wasobtained by reaction of 264 mg (1.0 mmol) of4-bromo-N,N-dimethylbenzenesulfonamide. After purification (SiO₂;Hexanes:EtOAc 1:1) 292 mg (quantitative yield) of pure product wereobtained as white solid. A solution of4-(6-methoxypyridin-3-yl)-N,N-dimethylbenzenesulfonamide (292 mg, 1.0mmol) in EtOH (4 ml) and HBr 48% (4 ml) was stirred at 80° C. overnight.The solvent was evaporated and the crude compound (as hydrobromide salt)was purified by flash chromatography (DCM:MeOH 9:1). 278 mg wereobtained as a pale yellow solid (quantitative yield).

Following general procedure H1A, compound 483 was prepared from thisintermediate in 79% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 8.15 (d, 1H),8.02 (dd, 1H), 7.92 (m, 2H), 7.74 (m, 2H), 7.40-7.60 (m, 5H), 6.64 (d,1H), 2.62 (s, 6H)

Synthesis of Compound 484

Following general procedure H1A and similar to compound 482, compound484 was prepared in 56% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 10.14 (s,1H), 8.12 (d, 1H), 7.93-8.04 (m, 2H), 7.91 (s, 1H), 7.73-7.79 (m, 1H),7.54-7.73 (m, 3H), 7.46 (dd, 1H), 7.09-7.21 (m, 1H), 6.63 (d, 1H), 2.64(s, 6H), 2.07 (s, 3H)

Synthesis of Compound 485

Following general procedure H1A and similar to compound 483, compound485 was prepared in 53% yield. ¹H NMR (300 MHz, DMSO-d6) ppm 10.14 (s,1H), 8.14 (d, 1H), 7.98-8.08 (m, 1H), 7.86-7.98 (m, 2H), 7.69-7.79 (m,3H), 7.56-7.64 (m, 1H), 7.45 (dd, 1H), 7.15 (ddd, 1H), 6.63 (d, 1H),2.62 (s, 6H), 2.06 (s, 3H)

Synthesis of Compound 486

Following general procedure A, compound 486 was prepared in 58% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 9.69 (s, 1H), 7.70-7.85 (m,3H), 7.52-7.63 (m, 1H), 7.43 (t, 1H), 7.31 (dd, 1H), 7.07-7.19 (m, 2H),6.92 (dd, 1H), 6.84 (td, 1H), 6.53 (dd, 1H), 2.06 (s, 3H)

Synthesis of Compound 487

Following general procedure A, compound 487 was prepared in 56% yield.¹H NMR (300 MHz, DMSO-d6) ppm 10.12 (s, 1H), 7.86-8.00 (m, 2H),7.69-7.75 (m, 1H), 7.56-7.64 (m, 1H), 7.44 (t, 1H), 7.30 (t, 1H),7.08-7.21 (m, 3H), 6.77-6.90 (m, 1H), 6.57 (dd, 1H), 4.07 (q, 2H), 2.06(s, 3H), 1.32 (t, 3H)

Assessment of Biological Activity Example 1

Compounds were screened for their ability to inhibit the activity of p38MAP kinase in vitro using the Transcreener KinasePlus assay (Madison,Wis.). This assay determines p38 activity by measuring ATP consumptionin the presence of a relevant peptide substrate. This assay is commonlyused in the characterization of kinases (Lowrey and Kleman-Leyer, ExpertOpin Ther Targets 10(1):179-90 (2006)). The Transcreener KinasePlusassay measures the p38 catalyzed conversion of ATP to ADP using aflorescence polarization-based approach. The p38 reaction is performedas usual and stopped by addition of Stop-Detect reagents. These reagentshalt further conversion of ATP to ADP and facilitate quantification ofproduct ADP. Detection of ADP is made possible by an ADP-specificantibody and corresponding fluorescently labeled tracer in theStop-Detect mix. In the absence of ADP, the fluorescently labeled traceris bound by the ADP-specific antibody resulting in a complex with highfluorescence polarization (FP). Product ADP competes with thefluorescently labeled tracer for binding to the ADP-specific antibodyand results in lower fluorescence polarization.

p38 gamma was obtained from Millipore, Inc (Billerica, Mass.). p38 MAPKinases are recombinant human full-length proteins with anamino-terminal GST fusion, expressed in and purified from E. coli.Proteins were aliquoted and stored at −80° C. Assays for p38 activitywere performed in the presence of an EGF receptor peptide (sequenceKRELVEPLTPSGEAPNQALLR—SEQ ID NO: 1) that was obtained from MidwestBiotech (Fishers, Ind.). EGFR peptide was aliquoted and stored at −20°C.

p38 MAP kinase assays were performed using p38 assay buffer containing20 mM HEPES, pH 7.5, 10 mM MgCl₂, 2 mM DTT, 0.01% Triton X-100, 10%glycerol, and 0.0002% bovine serum albumin (BSA). This buffer wassupplemented with 10 μM ATP, 25 μM EGFR peptide and 1 nM p38-γ.Compounds were weighed and dissolved to a known final concentration inDMSO.

The assay and compound dilutions were conducted on a Janus liquidhandling platform (Perkin Elmer, Waltham, Mass.) at room temperature(about 25° C.). Compounds in DMSO were placed in column 1 of a CostarV-bottom 96 well plate and diluted serially across the plate (3.3×dilutions). Columns 11 and 12 contain DMSO only (no inhibitor). Eachcompound dilution was 30-fold higher than the desired finalconcentration. A daughter plate was created by placing 180 μL of p38assay buffer in each well of a second Costar V-bottom 96 well plate and20 μL of the diluted compound stocks in DMSO were transferred and mixed.The assay was conducted in a black Proxipate F-Plus 384 well plate(Perkin Elmer, Waltham, Mass.). All subsequent transfers were conductedusing a 96 well head such that the final assay was quad mapped with 4replicates of each reaction. 5 μL of the compound mixture wastransferred from the daughter plate to the assay plate. 5 μL of amixture containing enzyme and EGFR peptide at 3-fold the desired finalconcentration in p38 assay buffer was then added to the appropriatewells. The reactions in the final two columns of the 384 well platereceived a mixture of EGFR peptide in p38 assay buffer in the absence ofenzyme. These wells served as a control for complete inhibition ofenzyme. After the compound and EGFR/enzyme (or EGFR only) mixtures wereadded these component are preincubated for 5 minutes. The assay wasinitiated by addition of 5 μL ATP in p38 assay buffer with mixing. Thefinal reaction volume was 15 μL and the reaction was allowed to run for1 hour at room temperature. The reaction was stopped by addition of 5 μLof Transcreener Stop-Detect solution containing 8 nM ADP Far Red Tracerand 41.6 μg/mL ADP-Anti-body in 100 mM HEPES, pH 7.5, 0.8 M sodiumchloride, 0.04% BRIJ-35, and 40 mM EDTA. Following addition of theStop-Detect solution, the contents of the plate were mixed and incubatedfor 1 hour at room temperature.

The plates were read for fluorescence polarization (FP) on a PerkinElmerEnVision using 3 filters (Cy5 Ex 620/40; Cy5 Em FP P-pol 688 nm; Cy5 EmFP S-pol 688 nm), and a mirror (Cy5 FP D658/fp688). Each read wasintegrated for 100 flashes. The formula1000*(S−G*P)/(S+G*P)was used to convert the 2 emission readouts into mP; S=S-pol filtersignal, P=P-pol filter signal, and G=gain.

The mP output from the EnVision (a 384 matrix) was transferred to a plotof mP versus compound concentration. XLfit (IDBS, Guildford, England)was used to apply a 4-parameter logistic fit to the data and determinethe median inhibitory concentration (IC₅₀). Preferred compounds exhibitIC₅₀ values of between about 0.05 μM and about 10 μM, preferably about0.1 μM to about 5 μM.

Example 2

Compounds were screened for the ability to inhibit TNFα release fromTHP-1 cells stimulated with lipopolysaccharide (LPS) in vitro. Theability of compounds to inhibit TNFα release in this in vitro assay wascorrelated with the inhibition of p38 activity and TNFα expression invivo, and was therefore an indicator of potential in vivo therapeuticactivity (Lee et al. Ann. N.Y. Acad. Sci. 696:149-170 (1993); and Nature372:739-746 (1994)).

THP-1 cells from ATCC (TIB202) were maintained at 37° C., 5% CO₂ in RPMI1640 media (MediaTech, Herndon, Va.) containing 4.5 g/L glucose,supplemented with 10% fetal bovine serum, 1% penicillin/streptomycin and50 μM β-mercaptoethanol.

Test compounds were initially dissolved in DMSO. Compounds were thendiluted in DMSO for all subsequent dilutions. The compounds were dilutedin RPMI Media immediately prior the addition to the THP-1 cells to afinal concentration of 1.25% DMSO (v/v) upon addition to the cells.Compounds were tested at a final concentration on cells of 750 to 1000μM. Where data indicates it was appropriate compounds were tested at a5-10 fold lower concentration. The assay was performed under sterileconditions. THP-1 cells at a culture density of 6−8×10⁵ cells/mL werecollected and resuspended in the RPMI media at 1×10⁶ cells/mL. 100 μl ofresuspended cells were added to each well, which contained 100 μl ofRPMI medium with test compound. Test compounds were prepared at 2.5times the final concentration. Final DMSO concentration was no more than0.5% (v/v). Cells were preincubated with compound for 60 minutes at 37°C., 5% CO₂ prior to stimulation with lipopolysaccharide (LPS) (SigmaL-2880, 1 mg/ml stock in PBS). The final LPS concentration in each wellwas 200 ng/ml for TNFα release. Unstimulated control cell suspensionsreceived DMSO/RPMI Media vehicle only. Cell mixtures were incubated for4 hours for TNFα release. 80 μl of supernatants were taken andtransferred to a fresh plate and stored at −70° C. until furtheranalysis. TNFα levels were measured using ELISA kits (R&D systemsPDTA00C). A SpectraMAX M5 was used as the plate reader. The calculatedamount of TNFα released was expressed as a percentage of the vehicle+LPScontrol.

Some compounds were tested for a TNFα dose response. Test compounds wereinitially dissolved in DMSO. Compounds were then serially diluted inDMSO over an appropriate range of concentrations between 2 mM and 4 μM.The compounds were diluted in RPMI Media immediately prior the additionto the THP-1 cells to a final concentration of 0.5% DMSO (v/v) uponaddition to the cells. The assay was performed under sterile conditions.THP-1 cells at a culture density of 6−8×10⁵ cells/mL were collected andresuspended in the RPMI media at 1×10⁶ cells/mL. 100 μl of resuspendedcells were added to each well, which contained 100 μl of RPMI media withtest compound. Test compounds were prepared at 2.5 times the finalconcentration. Final DMSO concentration was no more than 0.5% (v/v).Cells were preincubated with compound for 60 minutes at 37° C., 5% CO₂prior to stimulation with lipopolysaccharide (LPS) (Sigma L-2880, 1mg/ml stock in PBS). The final LPS concentration in each well was 200ng/ml for TNFα release. Unstimulated control cell suspensions receivedDMSO/RPMI Media vehicle only. Cell mixtures were incubated for 4 hoursfor TNFα release. 80 μl of supernatants were taken and transferred to afresh plate and stored at −70° C. until further analysis. TNFα levelswere measured using ELISA kits (R&D systems PDTA00C). A SpectraMAX M5was used as the plate reader. Analysis was performed by non-linearregression to generate a dose response curve. The calculated IC₅₀ valuewas the concentration of the test compound that caused a 50% decrease inTNFα levels.

Compounds inhibit the release of TNFα in this in vitro assay. Preferredcompounds exhibit IC₅₀ values for TNFα between about 1 μM and about 1000μM, preferably about 1 μM to about 800 μM.

Example 3

Compounds were tested for cytotoxicity using an ATPlite assay (PerkinElmer 6016731). THP-1 cells were treated with compounds as described forTNFα tests. 4 hours after LPS addition, 80 μl of media is removed forELISA. 48 hrs after LPS addition of media and cells were mixed with 100μl of ATPlite reagent. The mixture was shaken for 2 minutes then readfor luminescence. A SpectraMAX M5 is used as the plate reader.

The calculated cytotoxicity is expressed as a percentage of the LPS/DMSOcontrol compound. Compounds which had a low score in ATPlite compared tothe LPS/DMSO control were classified as cytotoxic rather than TNFαinhibitors. Where appropriate compounds were tested at 5-10 fold lowerconcentrations to determine whether the compound had activity at lower,non cytotoxic concentrations.

For serial dilutions of compound, analysis is performed by non-linearregression to generate a dose response curve. The calculated CC₅₀ valueis the concentration of the test compound that causes a 50% decrease inATP levels.

Compounds may exhibit cytotoxicity which can also lower TNFα release inthis in vitro assay. Preferred compounds show an ATPlite value which is100% of the LPS/DMSO control. Preferred compounds exhibit CC₅₀ values ofgreater than 1 mM, preferably of undetectable toxicity.

Example 4

Compounds are screened for the ability to inhibit TNFα release fromprimary human peripheral blood mononuclear cells (PBMC) stimulated withlipopolysaccharide (LPS) in vitro. The ability of compounds to inhibitTNFα release in this in vitro assay is correlated with the inhibition ofp38 activity and is therefore an indicator of potential in vivotherapeutic activity (Osteoarthritis & Cartilage 10:961-967 (2002); andLaufer, et al., J. Med. Chem 45: 2733-2740 (2002)).

Human peripheral blood mononuclear cells (PBMC) are isolated bydifferential centrifugation through a Ficoll-HyPaque density gradientfrom pooled serum of 3-8 individual blood donors. Isolated PBMC containapproximately 10% CD-14 positive monocytes, 90% lymphocytes and <1%granulocytes and platelets. PBMC (106/ml) are cultured in polystyreneplates and stimulated with lipopolysaccharide (LPS; 50 ng/ml; Sigma, St.Louis, Mo.) in the presence and absence of the test compound in serialdilutions, in duplicate, for 24 hr at 37° C. in GIBCO™ RPM1 medium(Invitrogen, Carlsbad, Calif.) without serum. The TNFα level in cellsupernatants is determined by ELISA using a commercially available kit(MDS Panlabs #309700).

Preferred compounds inhibit the release of TNFα in this assay with anIC₅₀ value of between about 100 μM and about 1000 μM, preferably about200 μM to about 800 μM.

Example 5

Compounds are screened for the ability to inhibit the release of TNFα inan in vivo animal model (See, e.g., Griswold et al. Drugs Exp. Clin.Res. 19:243-248 (1993); Badger, et al. J. Pharmacol. Exp. Ther.279:1453-1461 (1996); Dong, et al. Annu. Rev. Immunol. 20:55-72 (2002)(and references cited therein); Ono, et al., Cellular Signalling 12:1-13(2000) (and references cited therein); and Griffiths, et al. Curr.Rheumatol. Rep. 1:139-148 (1999)).

Without being bound by any particular theory, it is believed thatinhibition of TNFα in this model is due to inhibition of p38 MAP kinaseby the compound.

Male Sprague-Dawley rats (0.2-0.35 kg) are randomly divided into groupsof six or more and are dosed intravenously by infusion or bolusinjection, or are dosed orally with test compounds in a suitableformulation in each case. At ten minutes to 24 hr following treatmentlipopolysaccharide E. coli/0127:B8 (0.8 mg/kg) is administered IV in thepresence of D-galactosamine. Blood levels are samples are collected 1.5hours post-treatment with LPS. Serum TNFα and/or IL-6 determined usingan appropriate ELISA kit and compared to that from vehicle-treatedcontrol.

Preferred compounds inhibit the release of TNFα in this in vivo assay.Preferred compounds exhibit an ED₅₀ value of less than 500 mg/kg,preferably less than 400 mg/kg, preferably less than 200 mg/kg,preferably less than 100 mg/kg, more preferably, less than 50 mg/kg,more preferably, less than 40 mg/kg, more preferably, less than 30mg/kg, more preferably, less than 20 mg/kg, more preferably, less than10 mg/kg.

The methods of determining the IC₅₀ of the inhibition of p38 by acompound include any methods known in the art that allow thequantitative detection of any of the downstream substrates of p38 MAPKas described above. Therefore, these methods additionally include butlimited to detection of expression of genes known to be regulated by p38either individually, or by gene arrays.

Results of Biological Tests

The data sets for each compound assayed as described in Examples 2 (TNFαinhibition) and 3 (ATPlite assay), above were binned based on percentageof control (POC) data. For a subset of compounds with data from doseresponse curves, calculated POC values at the 750 μM screeningconcentration were derived from the existing EC₅₀, CC₅₀ and Hill Slopevalues using the standard four-paramater curve fit equation assuming anupper asymptope of 100% and a lower asymptope of 0%. The relevantequations are: POC_(TNFα)=(100−0)/(1+(750/EC₅₀)^Hill Slope) andPOC_(ATPlite)=(100−0)/(1+(750/CC₅₀)^Hill Slope). These values wereaveraged with existing POC determinations create a data set that couldbe appropriately binned.

Data were binned using the following criteria: Bin A (greatestinhibition) POC<33; Bin B POC 33 and <66; Bin C 66-100, with eitherATPlite POC>90 or an ATPlite POC at least two-fold above the TNFα POC.When ATPlite POC for a given compound was not either 1) greater than 90,or 2) at least two-fold above the TNFα POC the compound was placed inbin C regardless of the TNFα POC. Adjustments were made to the binningof compounds 10, 21, 47, 160, 179, 189, 193, based on full dose responsecurves with CC₅₀:EC₅₀ ratios that were either >2 or <2, respectively. Inthe former case, the compounds were left in the appropriate bin based onTNFα POC and in the latter case they were placed in bin C.

TABLE 2 Example Bin 1 A 2 C 3 C 4 C 5 C 6 A 7 C 8 B 9 C 10 C 11 C 12 C13 C 14 C 15 C 16 C 17 C 18 B 19 A 20 C 21 C 22 A 23 C 24 C 25 C 26 C 27C 28 C 29 A 30 C 31 C 32 C 33 C 34 C 35 C 36 C 37 C 38 C 39 C 40 C 41 A42 C 43 C 44 C 45 C 46 C 47 A 48 C 49 C 50 B 51 C 52 C 53 C 54 C 56 C 58C 59 C 60 A 61 C 62 C 63 C 64 C 65 C 66 C 67 C 68 C 69 C 70 C 72 A 73 A74 A 75 C 77 C 78 C 79 C 80 A 81 C 82 A 83 C 84 A 85 C 86 C 87 C 88 C 89A 90 B 91 C 92 C 93 A 94 A 96 A 97 A 98 C 99 C 100 C 101 C 102 A 103 C104 C 105 A 106 A 107 C 108 C 109 A 110 C 111 C 112 C 113 C 114 B 115 C116 C 117 A 118 A 119 C 120 B 121 A 122 C 123 C 124 C 125 C 126 C 127 B128 A 129 B 130 A 131 C 132 A 133 C 134 C 135 A 136 A 137 A 138 A 139 A140 B 141 A 142 C 143 C 144 C 145 A 147 A 148 C 149 C 150 C 151 C 152 A153 A 154 C 155 A 156 C 158 C 159 A 160 C 161 C 162 C 163 B 164 C 166 C167 B 168 B 169 A 171 C 172 A 173 C 174 C 177 A 178 A 179 C 182 C 183 A184 C 185 C 186 C 187 C 188 C 189 B 190 C 192 C 193 B 195 C 197 C 200 A201 C 202 C 203 A 209 C 210 C 211 A 212 C 213 C 214 A 215 C 216 B 217 A218 C 219 C 220 C 221 C 222 C 223 C 224 C 225 B 226 C 227 C 228 A 229 C230 C 231 C 232 B 233 C 234 C 235 A 236 A 237 C 238 B 239 C 240 B 241 A242 A 243 C 244 C 245 A 246 C 247 C 248 C 249 A 250 B 251 C 252 A 253 C254 A 255 C 256 C 257 A 258 A 259 C 260 B 261 C 262 B 263 C 264 C 265 C266 C 267 A 268 A 269 C 270 C 271 C 272 A 273 A 274 A 275 C 276 C 277 A278 A 279 A 280 C 281 C 282 B 283 A 284 C 285 A 286 C 287 B 288 A 289 C290 A 291 A 292 C 293 C 294 A 295 A 296 C 297 C

While the present invention has been described in some detail forpurposes of clarity and understanding, one skilled in the art willappreciate that various changes in form and detail can be made withoutdeparting from the true scope of the invention. All figures, tables,appendices, patents, patent applications and publications, referred toabove, are incorporated herein by reference.

What is claimed:
 1. A method of treating an inflammatory condition,comprising administering to a patient in need thereof a compound offormula I

wherein M is CR¹; A is CR²; L is CR³; B is CR⁴; E is CX⁴; G is CX³; J isCX²; K is CX¹; wherein each dashed line is a double bond; R¹ is selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl,cyano, sulfonamido, halo, aryl, alkenylenearyl, and heteroaryl; R² isselected from the group consisting of aryl; unsubstituted heteroaryl;heteroaryl substituted with one or more substituents selected from halo,alkyl, alkenyl, OCF₃, NO₂, OH, alkoxy, haloalkoxy, amino, CO₂H,CO₂alkyl, and heteroaryl; cycloalkyl; unsubstituted cycloheteroalkyl andcycloheteroalkyl substituted with one to three substituentsindependently selected from alkyleneOH, C(O)NH₂, NH₂, oxo (═O), aryl,haloalkyl, halo, and OH; R³ is selected from the group consisting ofhydrogen, aryl, alkenylenearyl, heteroaryl, alkyl, alkenyl, haloalkyl,amino, and hydroxy; R⁴ is selected from the group consisting ofhydrogen, alkyl, haloalkyl, alkoxy, aryl, alkenyl, alkenylenearyl, andheteroaryl; and X¹, X², X³, X⁴, and X⁵ are independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, halo, hydroxy, amino,aryl, cycloalkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl,cyano, aldehydo, alkylcarbonyl, amido, haloalkylcarbonyl, sulfonyl, andsulfonamide, or X² and X³ together form a 5- or 6-membered ringcomprising —O(CH₂)O—, wherein n is 1 or 2, wherein at least one of X¹,X², X³, X⁴, and X⁵ is not hydrogen; and wherein at least one of (a) to(e) is satisfied: (a) at least one of X¹, X², X³, X⁴, and X⁵ is notselected from the group consisting of halo, alkoxy, and hydroxy; (b) R¹is not selected from the group consisting of hydrogen, alkyl, alkenyl,phenyl, substituted phenyl and halo; (c) R² is not phenyl or substitutedphenyl; (d) R³ is not selected from the group consisting of hydrogen,alkyl, alkenyl, haloalkyl, hydroxy, phenyl and substituted phenyl; (e)R⁴ is not selected from the group consisting of hydrogen, alkyl,haloalkyl, alkoxy, alkenyl, phenyl and substituted phenyl; or apharmaceutically acceptable salt, ester, or solvate thereof.
 2. Themethod of claim 1, wherein at least one of X¹, X², or X³ is haloalkoxy.3. The method of claim 1, wherein R¹ is selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, alkenyl, cyano, sulfonamido,halo, alkenylenearyl, and heteroaryl; R² is selected from the groupconsisting of aryl; unsubstituted heteroaryl; heteroaryl substitutedwith one or more substituents selected from halo, unsubstituted alkyl,alkenyl, OCF₃, NO₂, OH, alkoxy, haloalkoxy, amino, CO₂H, and CO₂alkyl;cycloalkyl; unsubstituted cycloheteroalkyl and cycloheteroalkylsubstituted with one to three substituents independently selected fromalkyleneOH, C(O)NH₂, NH₂, aryl, haloalkyl, halo, and OH; R⁴ is selectedfrom the group consisting of hydrogen, haloalkyl, alkoxy, alkenyl, andalkenylenearyl; and X⁵ is hydrogen.
 4. The method of claim 1, whereinone of X¹, X², and X³ is not hydrogen.
 5. The method of claim 4, whereinR² is selected from the group consisting of aryl; unsubstitutedheteroaryl; heteroaryl substituted with one or more substituentsselected from halo, unsubstituted alkyl, alkenyl, OCF₃, NO₂, OH, alkoxy,haloalkoxy, amino, CO₂H, and CO₂alkyl; cycloalkyl; and unsubstitutedcycloheteroalkyl.
 6. The method of claim 5, wherein the compound offormula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 7. The method of claim 1,wherein R² is selected from the group consisting of 4-pyridyl,cyclopropanyl, 2-furanyl, 4-(3,5-dimethyl)-isoxazolyl, 4-pyrazolyl,4-(1-methyl)-pyrazolyl, 5-pyrimidinyl, 2-imidazolyl, and thiazolyl. 8.The method of claim 1, wherein at least one of X¹, X², or X³ is alkyl orcycloalkyl.
 9. The method of claim 1, wherein at least one of X¹, X², orX³ is haloalkyl.
 10. The method of claim 1, wherein at least one of X¹,X², or X³ is alkenyl.
 11. The method of claim 1, wherein at least one ofX¹, X², or X³ is amino.
 12. A method of treating an inflammatorycondition, comprising administering to a patient in need thereof acompound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 13. The method of claim1, wherein the compound exhibits an IC₅₀ in a range of about 100 μM toabout 1000 μM for inhibition of p38 MAPK.
 14. The method of claim 13,wherein the IC₅₀ is in the range of about 200 μM to about 800 μM. 15.The method of claim 1, wherein the compound exhibits an EC₅₀ in therange of about 0.1 μM to about 1000 μM for inhibition of TNFα secretionin a bodily fluid in vivo.
 16. The method of claim 1, wherein theinflammatory condition is selected from the group consisting offibrosis; chronic obstructive pulmonary disease; inflammatory pulmonaryfibrosis; rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis;gout; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxicshock syndrome; myofacial pain syndrome; Shigellosis; asthma; adultrespiratory distress syndrome; inflammatory bowel disease; Crohn'sdisease; psoriasis; eczema; ulcerative colitis; glomerular nephritis;scleroderma; chronic thyroiditis; Grave's disease; Ormond's disease;autoimmune gastritis; myasthenia gravis; autoimmune hemolytic anemia;autoimmune neutropenia; thrombocytopenia; pancreatic fibrosis; chronicactive hepatitis; hepatic fibrosis; renal disease; renal fibrosis;irritable bowel syndrome; pyresis; restenosis; cerebral malaria; strokeinjury; ischemic injury; neural trauma; Alzheimer's disease;Huntington's disease; Parkinson's disease; acute pain; chronic pain;allergies; cardiac hypertrophy; chronic heart failure; acute coronarysyndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease;Reiter's syndrome; acute synoviitis; muscle degeneration; bursitis;tendonitis; tenosynoviitis; herniated, ruptured, or prolapsedintervertebral disk syndrome; osteopetrosis; thrombosis; silicosis;pulmonary sarcosis; bone resorption disease; cancer; Multiple Sclerosis;lupus; fibromyalgia; AIDS; Herpes Zoster; Herpes Simplex; influenzavirus; Severe Acute Respiratory Syndrome; cytomegalovirus; diabetesmellitus and combinations thereof.
 17. The method of claim 16, whereinthe inflammatory condition is fibrosis.
 18. The method of claim 17,wherein the fibrosis is pulmonary fibrosis.
 19. A method of treating aninflammatory condition, comprising administering to a patient in needthereof a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 20. The method of claim19, wherein the inflammatory condition is selected from the groupconsisting of fibrosis; chronic obstructive pulmonary disease;inflammatory pulmonary fibrosis; rheumatoid arthritis; rheumatoidspondylitis; osteoarthritis; gout; sepsis; septic shock; endotoxicshock; gram-negative sepsis; toxic shock syndrome; myofacial painsyndrome; Shigellosis; asthma; adult respiratory distress syndrome;inflammatory bowel disease; Crohn's disease; psoriasis; eczema;ulcerative colitis; glomerular nephritis; scleroderma; chronicthyroiditis; Grave's disease; Ormond's disease; autoimmune gastritis;myasthenia gravis; autoimmune hemolytic anemia; autoimmune neutropenia;thrombocytopenia; pancreatic fibrosis; chronic active hepatitis; hepaticfibrosis; renal disease; renal fibrosis; irritable bowel syndrome;pyresis; restenosis; cerebral malaria; stroke injury; ischemic injury;neural trauma; Alzheimer's disease; Huntington's disease; Parkinson'sdisease; acute pain; chronic pain; allergies; cardiac hypertrophy;chronic heart failure; acute coronary syndrome; cachexia; malaria;leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acutesynoviitis; muscle degeneration; bursitis; tendonitis; tenosynoviitis;herniated, ruptured, or prolapsed intervertebral disk syndrome;osteopetrosis; thrombosis; silicosis; pulmonary sarcosis; boneresorption disease; cancer; Multiple Sclerosis; lupus; fibromyalgia;AIDS; Herpes Zoster; Herpes Simplex; influenza virus; Severe AcuteRespiratory Syndrome; cytomegalovirus; diabetes mellitus andcombinations thereof.
 21. The method of claim 20, wherein theinflammatory condition is fibrosis.
 22. The method of claim 21, whereinthe fibrosis is idiopathic pulmonary fibrosis.